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Stroke has become a global problem due to high prevalence and economic burden all around the world. Stroke incidence varies among countries, ranging around 200 per100,000 person-year, and is the second leading cause of death  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_1" \o "Ovbiagele, 2011 #11" 1,  HYPERLINK \l "_ENREF_2" \o "Soler, 2010 #38" 2]. From the latest assessment for Global Burden of Disease (GBD) in 2010, stroke also ranks number 3 to cause disability that poses significant economic burden  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_3" \o "Evers, 2004 #40" 3,  HYPERLINK \l "_ENREF_4" \o "Murray, 2013 #41" 4]. Mortality rate of stroke patient is correlated with treatment accessibility in the golden hours, when patient most benefited with thrombolytic treatment within first 4.5 hours. With adequate treatment in golden hours, patients have higher chance to survive  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_5" \o "Saver, 2010 #51" 5]. However, survived patients after stroke attack still face multi-years or even permanent disability. Therefore, understanding of underlying process of post-stroke brain remodeling is quite important to improve recovery after stroke attack.

Ischemic stroke is more prevalent than hemorrhagic stroke in adult, comprises to 80-85% of stroke incidences  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_6" \o "Roach, 2008 #64" 6]. It is already well-known that after ischemic stroke, focal brain fibrosis will be found in the ischemic core. Fibrotic tissue is the result of healing mechanism, by which ischemic core is patched through generation of fibrous extracellular matrix. Even though scarring may seal the injured brain tissue, excessive fibrous formation may alter the structure and function of the brain. Excessive scarring also has detrimental effect in inhibiting axonal growth for neuronal plasticity  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_7" \o "Wanner, 2008 #2469" 7]. Therefore, long term effect of excessive scarring also correlates to poorer recovery rate  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_8" \o "Fernandez-Klett, 2013 #79" 8,  HYPERLINK \l "_ENREF_9" \o "Badan, 2003 #2551" 9]. 

Focal brain scarring in ischemic core is the end result of activated astrocytes that produce excessive amount of fibrous extra cellular matrix (ECM)  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "Stipursky, 2007 #3233" 10]. More recent evidence highlighted the importance of neurovascular unit in brain scarring after ischemic stroke. Study from clinical specimens of ischemic stroke patients found that neurovascular unit were lost after acute stroke and then followed by migration and rapid proliferation of vascular pericytes that increased the total pool of fibrous ECM producing cells  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_8" \o "Fernandez-Klett, 2013 #79" 8]. However, the loss of endothelium in correlation to pericyte recruitment and excessive proliferation of fibrous connective tissue is still unclear. Under ischemia condition, production of matrix degrading enzymes is also increased to degrade vasculature basement membrane  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_11" \o "Alam, 2011 #583" 11]. Supporting evidence found that TGF-� can promote proliferation of recruited vascular mural cells and surrounding astrocytes that cause brain scarring  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_12" \o "Schachtrup, 2010 #2536" 12,  HYPERLINK \l "_ENREF_13" \o "Beck, 2012 #2544" 13]. In addition to inflammatory cells, several non-inflammatory cells, including endothelium, are also able to secrete TGF-� in ischemia condition  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_14" \o "Li, 2005 #3238" 14]. Moreover, laminin that is one of main matrix produced by endothelium was significantly deposited in ischemic core  ADDIN EN.CITE <EndNote><Cite><Author>Vaananen</Author><Year>2008</Year><RecNum>3234</RecNum><DisplayText>[15]</DisplayText><record><rec-number>3234</rec-number><foreign-keys><key app="EN" db-id="wtefz5zpvzae2qe50vrx5dadxeepf5f0rpxe">3234</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vaananen, A.</author><author>Risteli, J.</author><author>Liesi, P.</author></authors></contributors><auth-address>The Brain Laboratory, Department of Biological and Environmental Sciences, University of Helsinki, Helsinki, Finland.</auth-address><titles><title>Spatial and temporal distribution of laminins in permanent focal ischemic brain damage of the adult rat</title><secondary-title>J Neurosci Res</secondary-title><alt-title>Journal of neuroscience research</alt-title></titles><periodical><full-title>J Neurosci Res</full-title><abbr-1>Journal of neuroscience research</abbr-1></periodical><alt-periodical><full-title>J Neurosci Res</full-title><abbr-1>Journal of neuroscience research</abbr-1></alt-periodical><dates><year>2008</year><pub-dates><date>May 23</date></pub-dates></dates><isbn>1097-4547 (Electronic)&#xD;0360-4012 (Linking)</isbn><accession-num>18500756</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/18500756</url></related-urls></urls><electronic-resource-num>10.1002/jnr.21723</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_15" \o "Vaananen, 2008 #3234" 15]. Based to these pieces of evidence, we hypothesize endothelium to regulate brain scarring through endothelial to mesenchymal transition (EndMT) and to block the process would decrease fibrosis that improve brain recovery.

EndMT was firstly discovered by developmental biologist as phenotypic transformation of endothelium into mesenchymal cell in embryogenesis, especially in heart formation and angiogenesis  ADDIN EN.CITE <EndNote><Cite><Author>Kovacic</Author><Year>2012</Year><RecNum>82</RecNum><DisplayText>[16]</DisplayText><record><rec-number>82</rec-number><foreign-keys><key app="EN" db-id="5x9teee9a0az27erfwpv50pv2wpstxx90azv">82</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kovacic, J. C.</author><author>Mercader, N.</author><author>Torres, M.</author><author>Boehm, M.</author><author>Fuster, V.</author></authors></contributors><auth-address>Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA. jason.kovacic@mountsinai.org</auth-address><titles><title>Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease</title><secondary-title>Circulation</secondary-title><alt-title>Circulation</alt-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><alt-periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></alt-periodical><pages>1795-808</pages><volume>125</volume><number>14</number><keywords><keyword>Animals</keyword><keyword>Endothelium/*pathology</keyword><keyword>*Epithelial-Mesenchymal Transition</keyword><keyword>Fibrosis</keyword><keyword>Heart/*embryology</keyword><keyword>Heart Valves/embryology</keyword><keyword>Humans</keyword><keyword>Myocardium/pathology</keyword><keyword>Signal Transduction</keyword><keyword>T-Box Domain Proteins/physiology</keyword><keyword>Transforming Growth Factor beta/physiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr 10</date></pub-dates></dates><isbn>1524-4539 (Electronic)&#xD;0009-7322 (Linking)</isbn><accession-num>22492947</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22492947</url></related-urls></urls><custom2>3333843</custom2><electronic-resource-num>10.1161/CIRCULATIONAHA.111.040352</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_16" \o "Kovacic, 2012 #82" 16]. Recently, this process was also found to occur in adult diseases, including malignancies and fibrosis  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "Kovacic, 2012 #82" 16,  HYPERLINK \l "_ENREF_17" \o "Potenta, 2008 #84" 17]. In heart fibrosis, endothelial cells migrate under certain stimuli and gain mesenchymal phenotype to form myofibroblasts and to activate surrounding connective tissue in ischemic core  ADDIN EN.CITE <EndNote><Cite><Author>Kovacic</Author><Year>2012</Year><RecNum>82</RecNum><DisplayText>[16]</DisplayText><record><rec-number>82</rec-number><foreign-keys><key app="EN" db-id="5x9teee9a0az27erfwpv50pv2wpstxx90azv">82</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kovacic, J. C.</author><author>Mercader, N.</author><author>Torres, M.</author><author>Boehm, M.</author><author>Fuster, V.</author></authors></contributors><auth-address>Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA. jason.kovacic@mountsinai.org</auth-address><titles><title>Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease</title><secondary-title>Circulation</secondary-title><alt-title>Circulation</alt-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><alt-periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></alt-periodical><pages>1795-808</pages><volume>125</volume><number>14</number><keywords><keyword>Animals</keyword><keyword>Endothelium/*pathology</keyword><keyword>*Epithelial-Mesenchymal Transition</keyword><keyword>Fibrosis</keyword><keyword>Heart/*embryology</keyword><keyword>Heart Valves/embryology</keyword><keyword>Humans</keyword><keyword>Myocardium/pathology</keyword><keyword>Signal Transduction</keyword><keyword>T-Box Domain Proteins/physiology</keyword><keyword>Transforming Growth Factor beta/physiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr 10</date></pub-dates></dates><isbn>1524-4539 (Electronic)&#xD;0009-7322 (Linking)</isbn><accession-num>22492947</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22492947</url></related-urls></urls><custom2>3333843</custom2><electronic-resource-num>10.1161/CIRCULATIONAHA.111.040352</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_16" \o "Kovacic, 2012 #82" 16]. Eventhough EndMT in ischemic stroke is still unknown, recently EndMT was found in brain as an underlying mechanism of cerebral cavernous malformation  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_18" \o "Maddaluno, 2013 #701" 18]. Response to ischemic injury is initiated by hypoxia inducible factor-1 (HIF-1) system, especially by upregulating several target genes via specific DNA motif called hypoxia response element. HIF-1 is a heterodimer with � and � subunit, by which the �-subunit is tightly controlled by cellular oxygen tension. Under normal oxygen tension, HIF-1� protein is degraded by an oxygen-dependent mechanism. In contrast, under hypoxia condition, HIF-1� is prevented from degradation and translocated into nucleus to dimerize with � subunit. The active form of HIF-1 protein then transactivates target genes, such as vascular endothelial growth factor (VEGF) and transforming growth factor-� (TGF-�)  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_19" \o "Semenza, 2002 #310" 19,  HYPERLINK \l "_ENREF_20" \o "Lario, 2003 #103" 20]. VEGF signaling is able to promote endothelial cells proliferation, filopodial extension and ECM degradation. This signaling is positively regulated under hypoxia condition that may also occur in ischemic stroke  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_21" \o "Herbert, 2011 #85" 21]. Further, endothelial cells secret several factors such as platelet-derived growth factor � (PDGF�) and TGF-� to have autocrine effect to themselves and paracrine effects by recruitment and transformation of vascular mural cells to form fibroblast-like cells  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_8" \o "Fernandez-Klett, 2013 #79" 8,  HYPERLINK \l "_ENREF_21" \o "Herbert, 2011 #85" 21]. Finally, activation of vascular mural cells, astrocytes and surrounding connective tissue by TGF-� may form glial scarring that limits the axon sprouting for recovery  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_8" \o "Fernandez-Klett, 2013 #79" 8,  HYPERLINK \l "_ENREF_13" \o "Beck, 2012 #2544" 13]. In this study, we will specifically aim to investigate the importance of endothelium in pericytes recruitment and astrocytes activation through TGF-� secretion. We will also investigate the possibility of TGF-� inhibitor (pirfenidone) to decrease fibrosis and improve recovery after stroke.

TGF-� has been proven as important factor in several fibrosis diseases. Once it binds to the receptor, TGF-� would activate downstream Smad cascade to increase fibrous extracellular deposition, while inhibiting its degradation  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_22" \o "Akhurst, 2012 #2413" 22,  HYPERLINK \l "_ENREF_23" \o "Flanders, 2003 #11" 23]. Therefore, TGF-� inhibition is promising to reverse EndMT and resolving fibrosis. Application of Pirfenidone as a TGF-� inhibitor has been validated in several disease models  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_24" \o "Jung, 2012 #2547" 24-26]. In vivo application of pirfenidone successfully attenuates mesangial deposition and improves outcome in glomerulosclerosis patients  ADDIN EN.CITE <EndNote><Cite><Author>Yanagita</Author><Year>2012</Year><RecNum>87</RecNum><DisplayText>[27]</DisplayText><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="5x9teee9a0az27erfwpv50pv2wpstxx90azv">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yanagita, M.</author></authors></contributors><titles><title>Inhibitors/antagonists of TGF-beta system in kidney fibrosis</title><secondary-title>Nephrol Dial Transplant</secondary-title><alt-title>Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association</alt-title></titles><periodical><full-title>Nephrol Dial Transplant</full-title><abbr-1>Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association</abbr-1></periodical><alt-periodical><full-title>Nephrol Dial Transplant</full-title><abbr-1>Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association</abbr-1></alt-periodical><pages>3686-91</pages><volume>27</volume><number>10</number><keywords><keyword>Animals</keyword><keyword>Bone Morphogenetic Protein 7/agonists/antagonists &amp; inhibitors/physiology</keyword><keyword>Fibrosis</keyword><keyword>Humans</keyword><keyword>Kidney/drug effects/*pathology/physiopathology</keyword><keyword>Renal Insufficiency, Chronic/*drug therapy/physiopathology</keyword><keyword>Signal Transduction</keyword><keyword>Transforming Growth Factor alpha/*antagonists &amp; inhibitors/physiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1460-2385 (Electronic)&#xD;0931-0509 (Linking)</isbn><accession-num>23114895</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23114895</url></related-urls></urls><electronic-resource-num>10.1093/ndt/gfs381</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_27" \o "Yanagita, 2012 #87" 27]. In addition, application of TGF-� inhibitor also has already passed phase II clinical trial to inhibit excessive scar formation in patients with glaucoma and pulmonary fibrosis  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_28" \o "Siriwardena, 2002 #97" 28,  HYPERLINK \l "_ENREF_29" \o "Azuma, 2005 #2546" 29]. In this study we would target TGF-� signaling to decrease fibrous formation by EndMT process in ischemic stroke. Pirfenidone nanoparticle will be used to improve drug delivery across blood brain barrier in ischemia stroke model. Pirfenidone-PLGA has hydrophilic property that aimed for lower cytotoxicity, effective molecular size and zeta potential to pass through blood brain barrier. PLGA-nanosphere drugs were found to be effective for brain target and can be improved by several surface modifiers, such as polysorbate-80, chitosan and poloxomer-188  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_30" \o "Tahara, 2011 #289" 30,  HYPERLINK \l "_ENREF_31" \o "Gelperina, 2010 #296" 31]. As TGF--� is a potential target of therapy, the application of nanoparticle is also important to provide an opportunity of TGF-� inhibitor delivery through blood brain barrier. 


Discussion 
Neurorestoration in stroke
Stroke is the leading cause of disability and the third greatest burden of disease in the world  ADDIN EN.CITE <EndNote><Cite><Author>Murray</Author><Year>2013</Year><RecNum>41</RecNum><DisplayText>[4]</DisplayText><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="5x9teee9a0az27erfwpv50pv2wpstxx90azv">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Murray, C. J.</author><author>Lopez, A. D.</author></authors></contributors><auth-address>Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA 98121, USA. cjlm@uw.edu</auth-address><titles><title>Measuring the global burden of disease</title><secondary-title>N Engl J Med</secondary-title><alt-title>The New England journal of medicine</alt-title></titles><periodical><full-title>N Engl J Med</full-title><abbr-1>The New England journal of medicine</abbr-1></periodical><alt-periodical><full-title>N Engl J Med</full-title><abbr-1>The New England journal of medicine</abbr-1></alt-periodical><pages>448-57</pages><volume>369</volume><number>5</number><keywords><keyword>Cause of Death</keyword><keyword>Chronic Disease/epidemiology</keyword><keyword>*Cost of Illness</keyword><keyword>Disabled Persons/*statistics &amp; numerical data</keyword><keyword>Humans</keyword><keyword>Mortality</keyword><keyword>*Quality-Adjusted Life Years</keyword><keyword>United States/epidemiology</keyword><keyword>*World Health</keyword></keywords><dates><year>2013</year><pub-dates><date>Aug 1</date></pub-dates></dates><isbn>1533-4406 (Electronic)&#xD;0028-4793 (Linking)</isbn><accession-num>23902484</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23902484</url></related-urls></urls><electronic-resource-num>10.1056/NEJMra1201534</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_4" \o "Murray, 2013 #41" 4]. Once the patients are confirmed through clinical evaluation and brain imaging, whether they have ischemic or hemorrhagic stroke, current procedure in valuable golden period is very promising. With adequate intravenous thrombolytic therapy in the first 60 minutes, patients have greater opportunity to save threatened brain tissue and then sloping down after 4.5 hours. It is also mentioned that in large cerebral artery ischemia, for each minute delayed reperfusion, a million neurons die  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_5" \o "Saver, 2010 #51" 5]. Therefore, stroke treatment outcome is time dependent. Among patients who receive acute therapy, many of them still have significant long-term disability. For example, a study from third European Cooperative Acute Stroke Study, 47.6% of patients who received thrombolytic therapy had Rankin scale greater than 1, which means patients had slight to severe disabilities, at 90 days after acute therapy  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_37" \o "Hacke, 2008 #2380" 37]. Understanding of biological events in brain-repair mechanism is quite important to develop better restorative therapy for stroke patients. 

Progress has been made to understand neuroprotection and promote recovery after stroke attack. The concept of neuroprotection and neuron plasticity are now considering the concept of neurovascular unit, which neuroprotection cannot neglect the physiology of vascular compartment  ADDIN EN.CITE <EndNote><Cite><Author>Caplan</Author><Year>2011</Year><RecNum>2372</RecNum><DisplayText>[38]</DisplayText><record><rec-number>2372</rec-number><foreign-keys><key app="EN" db-id="wtefz5zpvzae2qe50vrx5dadxeepf5f0rpxe">2372</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Caplan, L. R.</author><author>Arenillas, J.</author><author>Cramer, S. C.</author><author>Joutel, A.</author><author>Lo, E. H.</author><author>Meschia, J.</author><author>Savitz, S.</author><author>Tournier-Lasserve, E.</author></authors></contributors><auth-address>Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. lcaplan@bidmc.harvard.edu</auth-address><titles><title>Stroke-related translational research</title><secondary-title>Arch Neurol</secondary-title><alt-title>Archives of neurology</alt-title></titles><periodical><full-title>Arch Neurol</full-title><abbr-1>Archives of neurology</abbr-1></periodical><alt-periodical><full-title>Arch Neurol</full-title><abbr-1>Archives of neurology</abbr-1></alt-periodical><pages>1110-23</pages><volume>68</volume><number>9</number><keywords><keyword>Animals</keyword><keyword>Cerebral Arterial Diseases/genetics/metabolism/pathology</keyword><keyword>Genome-Wide Association Study/methods/*trends</keyword><keyword>Humans</keyword><keyword>Mutation/genetics</keyword><keyword>Stroke/*genetics/metabolism/pathology</keyword><keyword>Translational Medical Research/methods/*trends</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1538-3687 (Electronic)&#xD;0003-9942 (Linking)</isbn><accession-num>21555605</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/21555605</url></related-urls></urls><custom2>3691989</custom2><electronic-resource-num>10.1001/archneurol.2011.99</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_38" \o "Caplan, 2011 #2372" 38]. Previously, the concept of neuroprotection only focused on protecting neurons and did not address neurovascular unit that may also involve in delayed damage. Neurovascular unit includes endothelial cells, vascular mural cells (pericytes or vascular smooth muscle cells), astrocytes and neurons associated with capillary smooth muscle. Components of vascular unit interact together with neurons and should be considered as an entity  ADDIN EN.CITE <EndNote><Cite><Author>Zhang</Author><Year>2012</Year><RecNum>2399</RecNum><DisplayText>[39]</DisplayText><record><rec-number>2399</rec-number><foreign-keys><key app="EN" db-id="wtefz5zpvzae2qe50vrx5dadxeepf5f0rpxe">2399</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhang, J. H.</author><author>Badaut, J.</author><author>Tang, J.</author><author>Obenaus, A.</author><author>Hartman, R.</author><author>Pearce, W. J.</author></authors></contributors><auth-address>Department of Neurosurgery, Loma Linda University School of Medicine, 11130 Anderson Street, Loma Linda, CA 92354, USA. jhzhang@llu.edu</auth-address><titles><title>The vascular neural network--a new paradigm in stroke pathophysiology</title><secondary-title>Nat Rev Neurol</secondary-title><alt-title>Nature reviews. Neurology</alt-title></titles><periodical><full-title>Nat Rev Neurol</full-title><abbr-1>Nature reviews. Neurology</abbr-1></periodical><alt-periodical><full-title>Nat Rev Neurol</full-title><abbr-1>Nature reviews. Neurology</abbr-1></alt-periodical><pages>711-6</pages><volume>8</volume><number>12</number><keywords><keyword>Brain/*blood supply/*physiopathology</keyword><keyword>Cerebrovascular Circulation/*physiology</keyword><keyword>Humans</keyword><keyword>Stroke/*physiopathology</keyword></keywords><dates><year>2012</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1759-4766 (Electronic)&#xD;1759-4758 (Linking)</isbn><accession-num>23070610</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23070610</url></related-urls></urls><custom2>3595043</custom2><electronic-resource-num>10.1038/nrneurol.2012.210</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_39" \o "Zhang, 2012 #2399" 39]. Neurovascular unit mainly function as blood brain barrier (BBB) that restricts toxic and harmful substances in the blood but allows water-soluble nutrients, and required molecules to brain parenchymes. Cells in this vascular compartment are anchored by vascular basement membrane, especially composed by fibronectin, laminin and collagen type IV. As of its importance, neurovascular unit is also the first affected compartment by any vascular injury. 

In brain physiology, pericyte contributes to regulation of blood flow by supporting the stsructure, maintenance and regulation of blood brain barrier. Pericyte also has multipotency character as mesenchymal stem cell to differentiate into several cell types  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_8" \o "Fernandez-Klett, 2013 #79" 8]. Along with pericyte, endothelium shares significant roles in regulation of blood brain barrier and tissue perfusion. Under certain regulation, endothelium conforms cellular migration, polarity and differentiation that is critical in response to stimuli  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_21" \o "Herbert, 2011 #85" 21]. During brain ischemia, vascular compartment is modulated by several secreted substances such as platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), cytokine (TGF-�), brain-derived neurotrophic factor (BDNF), angiopoeitin, adenosine and glutamate. Several studies have mentioned pericyte responses in acute phase of ischemic stroke. After ischemic attack, pericyte contraction affects capillary patency. Pericyte is very responsive to ischemia and is able to migrate to ischemic neural parenchyma that may play major role in injury response. Pericyte migration can be stimulated by several chemotactic factors. Extracellular adenosine triphosphate that is released by dying cells increases the contractility of pericyte and may stimulate early events by pericyte in acute phase  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_40" \o "Kawamura, 2003 #618" 40].

Pericyte migration can also be stimulated by TGF-� and PDGF  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_8" \o "Fernandez-Klett, 2013 #79" 8,  HYPERLINK \l "_ENREF_39" \o "Zhang, 2012 #2399" 39]. TGF-� promotes transition of pericyte into myofibroblast cells with activation of activated �-SM actin for migration ability. Further, rapid proliferation of pericytes is followed by extensive production of fibrous extracellular matrix. However the mechanism by which pericytes migration and proliferation are driven remains unclear. Eventhough fibrous matrix deposition is normal healing mechanism to patch injured parenchyma, excessive scarring formation may alter structure and functions of the brain. Hence, it also affects recovery of stroke patients. In cerebral angiogenesis, endothelium changes its conformation and polarity with mesenchymal properties. The migrating endothelium will then recruit pericyte to support new formed vessel. It is possible that pericyte migration and activation is correlated with endothelium activation. Therefore, in this study, we believe that pericyte migration may be driven by endothelium under specific regulation in response to ischemia (figure 1).

Endothelial-to-mesenchymal transition in post-ischemia
We propose the concept of endothelial-mesenchymal transition (EndMT) as the underlying mechanism of focal brain fibrosis after ischemic stroke. EndMT is a special type of epithelial-mesenchymal transition which involves endothelium. It was initially found in embryogenesis, especially during heart formation. Endothelial cells appear soon after primitive heart tube is formed. Endothelial cells then undergo phenotypic switching to mesenchymal phenotype. They invade the adjacent cardiac jelly to form endocardial cushion tissue around atrioventricular (AV) canal and outflow tract (OFT). OFT cushion is precursor of semilunar valves while AV cushions develop into Atrio-ventricular septum  ADDIN EN.CITE <EndNote><Cite><Author>Kovacic</Author><Year>2012</Year><RecNum>82</RecNum><DisplayText>[16]</DisplayText><record><rec-number>82</rec-number><foreign-keys><key app="EN" db-id="5x9teee9a0az27erfwpv50pv2wpstxx90azv">82</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kovacic, J. C.</author><author>Mercader, N.</author><author>Torres, M.</author><author>Boehm, M.</author><author>Fuster, V.</author></authors></contributors><auth-address>Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1030, New York, NY 10029, USA. jason.kovacic@mountsinai.org</auth-address><titles><title>Epithelial-to-mesenchymal and endothelial-to-mesenchymal transition: from cardiovascular development to disease</title><secondary-title>Circulation</secondary-title><alt-title>Circulation</alt-title></titles><periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></periodical><alt-periodical><full-title>Circulation</full-title><abbr-1>Circulation</abbr-1></alt-periodical><pages>1795-808</pages><volume>125</volume><number>14</number><keywords><keyword>Animals</keyword><keyword>Endothelium/*pathology</keyword><keyword>*Epithelial-Mesenchymal Transition</keyword><keyword>Fibrosis</keyword><keyword>Heart/*embryology</keyword><keyword>Heart Valves/embryology</keyword><keyword>Humans</keyword><keyword>Myocardium/pathology</keyword><keyword>Signal Transduction</keyword><keyword>T-Box Domain Proteins/physiology</keyword><keyword>Transforming Growth Factor beta/physiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Apr 10</date></pub-dates></dates><isbn>1524-4539 (Electronic)&#xD;0009-7322 (Linking)</isbn><accession-num>22492947</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22492947</url></related-urls></urls><custom2>3333843</custom2><electronic-resource-num>10.1161/CIRCULATIONAHA.111.040352</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_16" \o "Kovacic, 2012 #82" 16]. EndMT is also well known process in angiogenesis, when endothelial cells become tip cells with mesenchymal phenotype for vascular sprouting. Accumulating evidences recently report the involvement of EndMT process in adult diseases such as cancers and fibrosis in heart, kidney, eyes, and intestines  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_16" \o "Kovacic, 2012 #82" 16,  HYPERLINK \l "_ENREF_27" \o "Yanagita, 2012 #87" 27,  HYPERLINK \l "_ENREF_28" \o "Siriwardena, 2002 #97" 28]. However, EndMT importance in ischemic stroke is still unknown. 

Eventhough EndMT in ischemic stroke is still unknown, EndMT process does occur in adult brain following cerebral cavernous malformation (CCM) pathophysiology. In CCM, endothelial cells decrease their endothelial markers and gain some mesenchymal phenotypes. This process is also typical as fibrosis diseases by which thick, segmental basal layer with common gliotic tissue is formed  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_18" \o "Maddaluno, 2013 #701" 18]. In ischemic stroke, we propose that endothelial phenotypic switch occurs under ischemic stimuli. This response to ischemia may be initiated by HIF-1 system. The �-subunit of HIF-1 protein fails to be degraded by oxygen-dependent mechanism under ischemia. As the result, HIF-1� translocates into nucleus to form heterodimer with � subunit. Several target genes were reported following HIF-1 activation, such as: inducible nitric oxide synthase (iNOS), plasminogen activator, heme-oxygenase, p-21 and others that are important in cellular proliferation, differentiation and tissue remodelling. In ischemic kidney, HIF-1� activation particularly correlated to increased transcription of VEGF and TGF-� isoforms  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_20" \o "Lario, 2003 #103" 20]. We propose the EndMT process in ischemic stroke is also initiated by HIF-1 system that leads to VEGF and TGF-� upregulation. The secreted VEGF promotes EC proliferation, filopodial extension and extracellular matrix degradation. VEGF is positively regulated by hypoxia, rapidly expressed in response to tissue oxygen deficiency that may also occur in ischemic stroke  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_21" \o "Herbert, 2011 #85" 21]. Further, activated endothelial cells could secret several factors, including PDGF-� and TGF-�. PDGF-� attracts surrounding PDGFR-� positive pericytes while TGF-� also actovates surrounding astrocytes  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_10" \o "Stipursky, 2007 #3233" 10]. TGF-� promotes fibrous ECM deposition by increasing ECM production and preventing its degradation  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_8" \o "Fernandez-Klett, 2013 #79" 8,  HYPERLINK \l "_ENREF_21" \o "Herbert, 2011 #85" 21,  HYPERLINK \l "_ENREF_41" \o "Rolny, 2006 #2402" 41]. In order to understand endothelial importance in the process we can use STOCK Tie2GFPSato/J transgenic mice. Tie2GFP mice originate from FVB/NJ mice with green fluorescent protein (GFP) expression under control of specific endothelium tyrosine kinase (Tie2) promoter. These transgenic mice were firstly developed by Japan scientist to study vascular development. GFP is consistently expressed by endothelial cells during embryogenesis and throughout adulthood, allowing visualization of endothelium and vascular network on a single cell resolution. Moreover, we can also purify endothelial cells with a single step fluorescent activated cell sorting  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_42" \o "Motoike, 2000 #2409" 42]. Endothelial migration to ischemic core will be monitored from different time point after MCAO with confocal microscopy. The results can also be compared with fluorescent images of CD31+, CD13+, and PDGFR�+ cells to see possible colocalization. GFP-positive endothelial cells will be harvested from mice and then RNA and cytoplasmic protein lysate can be collected. Transcriptional and translational level of E-cadherin, fibronectin, PDGF-� and TGF� will be analyzed. Using this approach, the possible source of TGF-� and PDGF-� in ischemic core will be revealed. Transgenic mice that can be used to study the process have been available from The Jackson Laboratory ( HYPERLINK "http://www.jax.org" http://www.jax.org).  

TGF-� signaling in EndMT process
TGF-� is a family with diverse roles in cellular function including growth, differentiation, matrix production and immunomodulation. It has three different isoforms: TGF-�1, TGF-�2 and TGF-�3 that each has distinct roles. TGF-� signaling is mediated through complex receptor system such as endoglin, �-glycan, type I and type II TGF-�R. Once TGF-� attach to endoglin or glycan receptor, it is presented to type II TGF-� receptor. Further, type II TGF-� receptor (T�RII) phosphorylates type I TGF-� receptor (T�RI) to activate Smad downstream pathway. receptor-regulated Smad proteins (R-Smad), such as Smad 2 and Smad 3, are directly activated by T�RI to enter nucleus and regulate several genes transcription that are important in cellular fate commitment and matrix production  ADDIN EN.CITE <EndNote><Cite><Author>Flanders</Author><Year>2003</Year><RecNum>2411</RecNum><DisplayText>[23]</DisplayText><record><rec-number>2411</rec-number><foreign-keys><key app="EN" db-id="wtefz5zpvzae2qe50vrx5dadxeepf5f0rpxe">2411</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Flanders, K. C.</author><author>Burmester, J. K.</author></authors></contributors><auth-address>Laboratory of Cell Regulation and Carcinogenesis, National Institutes of Health, Bethesda, Maryland, USA.</auth-address><titles><title>Medical applications of transforming growth factor-beta</title><secondary-title>Clin Med Res</secondary-title><alt-title>Clinical medicine &amp; research</alt-title></titles><periodical><full-title>Clin Med Res</full-title><abbr-1>Clinical medicine &amp; research</abbr-1></periodical><alt-periodical><full-title>Clin Med Res</full-title><abbr-1>Clinical medicine &amp; research</abbr-1></alt-periodical><pages>13-20</pages><volume>1</volume><number>1</number><keywords><keyword>Animals</keyword><keyword>Autoimmune Diseases/*drug therapy</keyword><keyword>Humans</keyword><keyword>Reperfusion Injury/*drug therapy</keyword><keyword>Transforming Growth Factor beta/chemistry/*therapeutic use</keyword><keyword>Wounds and Injuries/*drug therapy</keyword></keywords><dates><year>2003</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1539-4182 (Print)&#xD;1539-4182 (Linking)</isbn><accession-num>15931280</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/15931280</url></related-urls></urls><custom2>1069016</custom2></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_23" \o "Flanders, 2003 #11" 23]. In CCM pathology, EndMT in brain pathology is Smad-dependent. The phenotype switching of endothelium is regulated by Smad-dependent TGF-� signaling. Hence, several transcription of several mesenchymal genes are upregulated by recruitment of transcription cofactor by Smad protein  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_18" \o "Maddaluno, 2013 #701" 18]. However, TGF-� can also signal through Smad independent pathway through PI3K, MAPK, TRAF6-TAK1 and RhoA pathway  ADDIN EN.CITE <EndNote><Cite><Author>Connolly</Author><Year>2012</Year><RecNum>2416</RecNum><DisplayText>[43]</DisplayText><record><rec-number>2416</rec-number><foreign-keys><key app="EN" db-id="wtefz5zpvzae2qe50vrx5dadxeepf5f0rpxe">2416</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Connolly, E. C.</author><author>Freimuth, J.</author><author>Akhurst, R. J.</author></authors></contributors><auth-address>UCSF Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, California 94143-0512, USA.</auth-address><titles><title>Complexities of TGF-beta targeted cancer therapy</title><secondary-title>Int J Biol Sci</secondary-title><alt-title>International journal of biological sciences</alt-title></titles><periodical><full-title>Int J Biol Sci</full-title><abbr-1>International journal of biological sciences</abbr-1></periodical><alt-periodical><full-title>Int J Biol Sci</full-title><abbr-1>International journal of biological sciences</abbr-1></alt-periodical><pages>964-78</pages><volume>8</volume><number>7</number><keywords><keyword>Animals</keyword><keyword>Antineoplastic Agents/therapeutic use</keyword><keyword>Humans</keyword><keyword>Neoplasms/drug therapy/*metabolism</keyword><keyword>Transforming Growth Factor beta/antagonists &amp; inhibitors/*metabolism</keyword></keywords><dates><year>2012</year></dates><isbn>1449-2288 (Electronic)</isbn><accession-num>22811618</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22811618</url></related-urls></urls><custom2>3399319</custom2><electronic-resource-num>10.7150/ijbs.4564</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_43" \o "Connolly, 2012 #2416" 43]. MAPK pathway for example, is modulated by TGF-�1 ligands in astrocyte differentiation. Recent evidence demonstrated that radial glia fate commitment is regulated by Smad-PI3K/MAPK crosstalk under TGF-� stimulation. Radial glia with TGF-� administration significantly increased pool of GFAP+ subpopulation, which then co-administration with MAPK inhibitor reversed this effect.  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_44" \o "Stipursky, 2012 #401" 44]. Therefore, brain scarring in response to ischemic stroke may be significantly modulataed by TGF-� signaling either through Smad-dependent or independent pathway. 

In further step of fibrosis formation, interaction of TGF-� with basic fibroblast growth factor (bFGF) and connective tissue growth factor (CTGF) are important to promote persistent fibrosis. In vivo skin fibrosis model with subcutaneous injection of TGF-� only resulted in transient fibrosis and injection of CTGF alone had little effect. However, co-administration of TGF-� with either basic bFGF or CTGF effectively promotes stable long term fibrosis  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_45" \o "Mori, 1999 #409" 45] . TGF-� promotes CTGF overexpression in fibroblast that normally not expressed, through Smad-3 dependent mechanism  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_46" \o "Leask, 2004 #410" 46]. Later, CTGF acts as downstream mediator of by increasing fibroblast proliferation, promoting transdifferentiation into myofibroblast and ECM deposition that maintain the fibrosis initiated by TGF-�, for example by sustaining promoter activity of collagen gene (COL1A2)  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_47" \o "Chujo, 2005 #413" 47]. CTGF also acts as chemotactic factor for PDGF-�R+ cells and inflammatory cells. This TGF-� and CTGF interaction was found in skin fibrosis  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_46" \o "Leask, 2004 #410" 46], myocardial fibrosis  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_48" \o "Koitabashi, 2007 #411" 48] and glomerulosclerosis of the kidney  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_49" \o "Zhang, 2004 #417" 49]. In brain parenchyma, CTGF is upregulated in serum induced astrocyte differentiation  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_50" \o "Obayashi, 2009 #419" 50] and bFGF expression is increased following ischemia  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_51" \o "Lin, 1997 #630" 51]. Eventhough bFGF is a neurotropic factor, it is also considered as differentiation factor for active astrocyte. Expression of bFGF starts to increase at 48 hours after stroke attack and remains high until chronic phase. The elevation of bFGF can also be detected in patient�s serum and can be used as prognosis factor as the elevation is in line with infarct size  ADDIN EN.CITE <EndNote><Cite><Author>Guo</Author><Year>2006</Year><RecNum>631</RecNum><DisplayText>[52]</DisplayText><record><rec-number>631</rec-number><foreign-keys><key app="EN" db-id="5x9teee9a0az27erfwpv50pv2wpstxx90azv">631</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Guo, H.</author><author>Huang, L.</author><author>Cheng, M.</author><author>Jin, X.</author><author>Zhao, Y.</author><author>Yi, M.</author></authors></contributors><auth-address>Department of Neurology, People&apos;s Hospital, Peking University, 11 Xi Zhi Men Nan Da Jie, Beijing 100044, China. guoh@bjmu.edu.cn</auth-address><titles><title>Serial measurement of serum basic fibroblast growth factor in patients with acute cerebral infarction</title><secondary-title>Neurosci Lett</secondary-title><alt-title>Neuroscience letters</alt-title></titles><periodical><full-title>Neurosci Lett</full-title><abbr-1>Neuroscience letters</abbr-1></periodical><alt-periodical><full-title>Neurosci Lett</full-title><abbr-1>Neuroscience letters</abbr-1></alt-periodical><pages>56-9</pages><volume>393</volume><number>1</number><keywords><keyword>Acute Disease</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Analysis of Variance</keyword><keyword>Cerebral Infarction/*blood</keyword><keyword>Enzyme-Linked Immunosorbent Assay/methods</keyword><keyword>Female</keyword><keyword>Fibroblast Growth Factor 2/*blood</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Severity of Illness Index</keyword><keyword>Statistics as Topic</keyword><keyword>Time Factors</keyword></keywords><dates><year>2006</year><pub-dates><date>Jan 23</date></pub-dates></dates><isbn>0304-3940 (Print)&#xD;0304-3940 (Linking)</isbn><accession-num>16229951</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/16229951</url></related-urls></urls><electronic-resource-num>10.1016/j.neulet.2005.09.043</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_52" \o "Guo, 2006 #631" 52]. We believe that several growth factors, such as CTGF and bFGF, are also important as downstream mediator of TGF-� induction in brain scarring after ischemic stroke. 

In order to develop best treatment strategy, time line of the molecular events in cellular transition of neurovascular unit is very important. In an ischemic stroke model, endothelial activation and pericyte migration occur within first day of acute phase. Compared to normal neurovascular unit, endothelial cells in ischemic region is activated and formed mesenchymal phenotype as tip cell morphology. This process can be seen within first hour with electron microscopy. At this time point, pericyte still remains in the position without any morphological changes. At 3 hours after ischemic attack pericyte is activated with phenotypic transition and migration ability. The separation of pericyte to the luminal surface indicates not only the migration but also the degradation of surrounding basement membrane  ADDIN EN.CITE <EndNote><Cite><Author>Duz</Author><Year>2007</Year><RecNum>499</RecNum><DisplayText>[53]</DisplayText><record><rec-number>499</rec-number><foreign-keys><key app="EN" db-id="5x9teee9a0az27erfwpv50pv2wpstxx90azv">499</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Duz, B.</author><author>Oztas, E.</author><author>Erginay, T.</author><author>Erdogan, E.</author><author>Gonul, E.</author></authors></contributors><auth-address>GATA Department of Neurosurgery, School of Medicine, Gulhane Military Medical Academy, Etlik, 06018 Ankara, Turkey.</auth-address><titles><title>The effect of moderate hypothermia in acute ischemic stroke on pericyte migration: an ultrastructural study</title><secondary-title>Cryobiology</secondary-title><alt-title>Cryobiology</alt-title></titles><periodical><full-title>Cryobiology</full-title><abbr-1>Cryobiology</abbr-1></periodical><alt-periodical><full-title>Cryobiology</full-title><abbr-1>Cryobiology</abbr-1></alt-periodical><pages>279-84</pages><volume>55</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Cell Movement</keyword><keyword>*Hypothermia, Induced</keyword><keyword>*Infarction, Middle Cerebral Artery</keyword><keyword>Male</keyword><keyword>Pericytes/*ultrastructure</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword></keywords><dates><year>2007</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1090-2392 (Electronic)&#xD;0011-2240 (Linking)</isbn><accession-num>17923122</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/17923122</url></related-urls></urls><electronic-resource-num>10.1016/j.cryobiol.2007.08.009</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_53" \o "Duz, 2007 #499" 53]. In vivo model of ischemic stroke model revealed the overexpression of MMP-2 and MMP-9 in ischemic region. Both in hyperthermic and normothermic conditions, MMPs production is started within first-4 hours after ischemic attack and is maintained to degrade vascular basement membrane of the infarcted microvessels  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_11" \o "Alam, 2011 #583" 11]. Therefore the cellular migration form vascular lining only occurs after three hours of ischemic attack. The increased production of MMPs is possibly orchestrated by cellular component of neuro-vascular unit. Endothelium is important source of MMPs and the production can be modulated by surrounding pericytes. Co-culture of endothelium and pericyte in vitro significantly increased the production of active MMPs measured by both zymography and fluorimetric assay  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_54" \o "Zozulya, 2008 #584" 54], the migrating endothelium and pericyte already gained mesenchymal phenotype with myofibroblast characteristics. Thus, the myofibroblasts increase the total pool of ECM producing cells and play important role in scarring process. Production of ECM in injured parenchyme is continuously maintained during subacute phase and will be stabilized by matured fibroblast through CTGF and bFGF signaling in later stage of subacute phase or chronic phase. Therefore, the focal brain scarring of stroke patients remains stable for long term.  

Possibility of TGF-� inhibitor as a novel drug candidate to resolve brain scarring
Even though TGF-� is one of promising modality for several diseases, especially to improve hard tissue healing and due to its immunosuppressive effects, inhibition of TGF� signaling has been developed to treat several fibrosis-related diseases including glomerulonephritis, liver cirrhosis, pulmonary fibrosis, keloids, and post-surgical scarring  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_23" \o "Flanders, 2003 #11" 23,  HYPERLINK \l "_ENREF_27" \o "Yanagita, 2012 #87" 27,  HYPERLINK \l "_ENREF_28" \o "Siriwardena, 2002 #97" 28]. In addition, because many tumors over-express TGF-� to mediate tumor metastases, blocking TGF-� may also beneficial to suppress tumor metastases. The mechanisms to block TGF-� activity are mediated by inhibition of ligand-receptor interaction and inhibition of intracellular downstream signaling. Inhibition of ligand-receptor interaction includes soluble T�RII fragment, soluble active or latent TGF-�, decorin, tranilast and neutralizing antibody. Inhibition of intracellular downstream signaling can be mediated by threonine kinase inhibitor, Smad-activation inhibitor and RNA-expression inhibitor such as anti-sense expression vectors or blocking oligonucleotides  ADDIN EN.CITE <EndNote><Cite><Author>Flanders</Author><Year>2003</Year><RecNum>11</RecNum><DisplayText>[23]</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="vtaz5avwftz2tferza8xz55vsa55azevxdw5">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Flanders, K. C.</author><author>Burmester, J. K.</author></authors></contributors><auth-address>Laboratory of Cell Regulation and Carcinogenesis, National Institutes of Health, Bethesda, Maryland, USA.</auth-address><titles><title>Medical applications of transforming growth factor-beta</title><secondary-title>Clin Med Res</secondary-title><alt-title>Clinical medicine &amp; research</alt-title></titles><pages>13-20</pages><volume>1</volume><number>1</number><keywords><keyword>Animals</keyword><keyword>Autoimmune Diseases/*drug therapy</keyword><keyword>Humans</keyword><keyword>Reperfusion Injury/*drug therapy</keyword><keyword>Transforming Growth Factor beta/chemistry/*therapeutic use</keyword><keyword>Wounds and Injuries/*drug therapy</keyword></keywords><dates><year>2003</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1539-4182 (Print)&#xD;1539-4182 (Linking)</isbn><accession-num>15931280</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/15931280</url></related-urls></urls><custom2>1069016</custom2></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_23" \o "Flanders, 2003 #11" 23].  

Impressive clinical application of TGF-� antagonist has been made in kidney fibrosis and post-trabeculotomy scarring treatment by Pirfenidone. Pirfinidone successfully attenuates mesangial deposition and improves outcome in glomerulosclerosis patients  ADDIN EN.CITE <EndNote><Cite><Author>Yanagita</Author><Year>2012</Year><RecNum>87</RecNum><DisplayText>[27]</DisplayText><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="5x9teee9a0az27erfwpv50pv2wpstxx90azv">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yanagita, M.</author></authors></contributors><titles><title>Inhibitors/antagonists of TGF-beta system in kidney fibrosis</title><secondary-title>Nephrol Dial Transplant</secondary-title><alt-title>Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association</alt-title></titles><periodical><full-title>Nephrol Dial Transplant</full-title><abbr-1>Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association</abbr-1></periodical><alt-periodical><full-title>Nephrol Dial Transplant</full-title><abbr-1>Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association</abbr-1></alt-periodical><pages>3686-91</pages><volume>27</volume><number>10</number><keywords><keyword>Animals</keyword><keyword>Bone Morphogenetic Protein 7/agonists/antagonists &amp; inhibitors/physiology</keyword><keyword>Fibrosis</keyword><keyword>Humans</keyword><keyword>Kidney/drug effects/*pathology/physiopathology</keyword><keyword>Renal Insufficiency, Chronic/*drug therapy/physiopathology</keyword><keyword>Signal Transduction</keyword><keyword>Transforming Growth Factor alpha/*antagonists &amp; inhibitors/physiology</keyword></keywords><dates><year>2012</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1460-2385 (Electronic)&#xD;0931-0509 (Linking)</isbn><accession-num>23114895</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/23114895</url></related-urls></urls><electronic-resource-num>10.1093/ndt/gfs381</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_27" \o "Yanagita, 2012 #87" 27]. TGF-� inhibition is now already in phase III clinical trial to inhibit excessive scar formation in post-trabeculotomy glaucoma patients  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_28" \o "Siriwardena, 2002 #97" 28]. Existing data exerts Pirfenidone (5-methyl-1-phenyl-2[1H]-pyridone) as a potential drug that has both anti-fibrotic and anti-inflammatory properties. In vitro, pirfinidone suppressed proliferation of fibroblast and inhibited matrix production, promoted collagenase relase from fibroblast through inhibition of PDGF and TGF-� release. Inhibition of TNF-� secretion was also observed under Pirfinidone treatment. The anti-inflammatory properties of Pirfinidone in clinical setting were seen as daily clinical dose of 2403 mg that reach reach Cmax of 14.7 �g/ml. In addition, pirfenidone may serve as anti-TGF-� signaling through inhibition of Smad protein translocation into nucleus  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_26" \o "Choi, 2012 #14" 26]. Therefore, Pirfinidone mechanism to inhibit TGF-� in fibrosis is mediated by both TGF-� secretion inhibition and Smad translocation attenuation. However, drug delivery to brain is more complex because it restricts substances to pass through blood brain barrier based on both molecular size and charge residue  ADDIN EN.CITE <EndNote><Cite><Author>Seelig</Author><Year>1994</Year><RecNum>2427</RecNum><DisplayText>[55]</DisplayText><record><rec-number>2427</rec-number><foreign-keys><key app="EN" db-id="wtefz5zpvzae2qe50vrx5dadxeepf5f0rpxe">2427</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Seelig, A.</author><author>Gottschlich, R.</author><author>Devant, R. M.</author></authors></contributors><auth-address>Biocenter of the University of Basel, Switzerland.</auth-address><titles><title>A method to determine the ability of drugs to diffuse through the blood-brain barrier</title><secondary-title>Proc Natl Acad Sci U S A</secondary-title><alt-title>Proceedings of the National Academy of Sciences of the United States of America</alt-title></titles><periodical><full-title>Proc Natl Acad Sci U S A</full-title><abbr-1>Proceedings of the National Academy of Sciences of the United States of America</abbr-1></periodical><alt-periodical><full-title>Proc Natl Acad Sci U S A</full-title><abbr-1>Proceedings of the National Academy of Sciences of the United States of America</abbr-1></alt-periodical><pages>68-72</pages><volume>91</volume><number>1</number><keywords><keyword>*Blood-Brain Barrier</keyword><keyword>Chromatography, High Pressure Liquid</keyword><keyword>Humans</keyword><keyword>Models, Chemical</keyword><keyword>Pharmaceutical Preparations/*chemistry/metabolism</keyword><keyword>Solubility</keyword><keyword>Surface Properties</keyword></keywords><dates><year>1994</year><pub-dates><date>Jan 4</date></pub-dates></dates><isbn>0027-8424 (Print)&#xD;0027-8424 (Linking)</isbn><accession-num>8278409</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/8278409</url></related-urls></urls><custom2>42887</custom2></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_55" \o "Seelig, 1994 #2427" 55]. Application of nanoparticle coated drug is one of the most promising drug delivery to traverse blood brain barrier  ADDIN EN.CITE <EndNote><Cite><Author>Vastag</Author><Year>2010</Year><RecNum>2430</RecNum><DisplayText>[56]</DisplayText><record><rec-number>2430</rec-number><foreign-keys><key app="EN" db-id="wtefz5zpvzae2qe50vrx5dadxeepf5f0rpxe">2430</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vastag, B.</author></authors></contributors><titles><title>Biotechnology: Crossing the barrier</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><alt-periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></alt-periodical><pages>916-8</pages><volume>466</volume><number>7309</number><keywords><keyword>Animals</keyword><keyword>Blood-Brain Barrier/*metabolism</keyword><keyword>Brain Diseases/*drug therapy</keyword><keyword>Catheters, Indwelling</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Glial Cell Line-Derived Neurotrophic Factor/administration &amp;</keyword><keyword>dosage/pharmacokinetics/therapeutic use</keyword><keyword>Humans</keyword><keyword>Injections, Intraventricular</keyword><keyword>Neurturin/administration &amp; dosage/genetics/therapeutic use</keyword><keyword>Parkinson Disease/drug therapy</keyword><keyword>Proteins/administration &amp; dosage/adverse effects/*pharmacokinetics/*therapeutic</keyword><keyword>use</keyword></keywords><dates><year>2010</year><pub-dates><date>Aug 19</date></pub-dates></dates><isbn>1476-4687 (Electronic)&#xD;0028-0836 (Linking)</isbn><accession-num>20725015</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/20725015</url></related-urls></urls><electronic-resource-num>10.1038/466916a</electronic-resource-num></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_56" \o "Vastag, 2010 #2430" 56]. 

Biodegradable particulate has been considered as promising candidate for brain-targeting drug carrier system. Poly lactic co-glycolic acid (PLGA) is one of biodegradable polymer that has been approved by US FDA for human clinical uses, in terms of its safety and property to achieve sustain release. In addition, drug loadad-PLGA nanoparticle (PLGA NP) also has effective zeta potential with effective particle size, and smooth surface that increase the possibility of the drug to pass through blood brain barrier. Moreover, in this study we will also use surface-modified PLGA NP to increase particle stability and pharmacodynamics of both drug and carrier. Studies of surface modification by surfactant application on PLGA NP have been done to monitor the parmacodynamic of the drugs in brain tissue. Several PLGA loaded drugs, including doxorubicin, loperamide and 6-coumarin fluorescent drug were monitored. Surface modification of PLGA NP with trimethylated chitosan (TMC), polysorbate-80 and poloxamer-188 effectively increased the availability across blood brain barrier after intravenous or intracarotid injection  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_30" \o "Tahara, 2011 #289" 30,  HYPERLINK \l "_ENREF_31" \o "Gelperina, 2010 #296" 31,  HYPERLINK \l "_ENREF_36" \o "Chowdhury, 2013 #2431" 36]. Therefore, in this study we will use surface-modified Pirfenidone loaded poly lactic co-glycolic acid (PLGA) nanoparticle that aims to facilitate penetration through blood brain barrier. 

Due to physiological expression of TGF-� in uncompromised cells, mode of delivery of TGF-� inhibitors or antagonist will be critical to get effects only in the desired system. Therefore, local administration, as opposed to systemic one, is more preferable. An example from a Phase I clinical trial with systemic administration of active TGF-� caused anemia and reversible nephrotoxicity in some patients  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_57" \o "Calabresi, 1998 #425" 57]. In addition, preference of active vs latent TGF-� ligand must also be considered. Active TGF-� produces more side effects than latent ligand because active ligand misses activation step that is tightly controlled in vivo  ADDIN EN.CITE <EndNote><Cite><Author>Flanders</Author><Year>2003</Year><RecNum>11</RecNum><DisplayText>[23]</DisplayText><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="vtaz5avwftz2tferza8xz55vsa55azevxdw5">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Flanders, K. C.</author><author>Burmester, J. K.</author></authors></contributors><auth-address>Laboratory of Cell Regulation and Carcinogenesis, National Institutes of Health, Bethesda, Maryland, USA.</auth-address><titles><title>Medical applications of transforming growth factor-beta</title><secondary-title>Clin Med Res</secondary-title><alt-title>Clinical medicine &amp; research</alt-title></titles><pages>13-20</pages><volume>1</volume><number>1</number><keywords><keyword>Animals</keyword><keyword>Autoimmune Diseases/*drug therapy</keyword><keyword>Humans</keyword><keyword>Reperfusion Injury/*drug therapy</keyword><keyword>Transforming Growth Factor beta/chemistry/*therapeutic use</keyword><keyword>Wounds and Injuries/*drug therapy</keyword></keywords><dates><year>2003</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1539-4182 (Print)&#xD;1539-4182 (Linking)</isbn><accession-num>15931280</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/15931280</url></related-urls></urls><custom2>1069016</custom2></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_23" \o "Flanders, 2003 #11" 23]. In spite of these problems, drugs targeting intracellular pathway of TGF-� provide more benefits than the risks. According to assessment report as adopted by committee for medicinal product for human use (CHMP) of European Medicines Agency that compiled all reported adverse events from the database of all clinical trials, Pirfenidone does not appear with serious adverse events which could be considered as life threatening. It is mentioned that the death rate of subjects with 2403 mg of Pirfenidone is lower than of placebo at 72 weeks of treatment. However, Pirfenidone was correlated with relatively mild adverse events in gastro intestinal system including nausea, vomiting, diarrhea, and dyspepsia. Risk of asthenia was also increased with Pirfenidone treatment but it was not in dose dependent fashion. In conclusion, Pirfenidone is potential drug that is relatively safe to treat tissue fibrosis  ADDIN EN.CITE <EndNote><Cite><Author>Agency</Author><Year>2010</Year><RecNum>10224</RecNum><DisplayText>[58]</DisplayText><record><rec-number>10224</rec-number><foreign-keys><key app="EN" db-id="5x9teee9a0az27erfwpv50pv2wpstxx90azv">10224</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>European Medicines Agency</author></authors></contributors><titles><title>CHMP assesment report: pirfenidone</title><secondary-title>Committee for Medicinal Products for Human Use (CHMP)</secondary-title></titles><periodical><full-title>Committee for Medicinal Products for Human Use (CHMP)</full-title></periodical><volume>EMA/CHMP/115147/2011</volume><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>[ HYPERLINK \l "_ENREF_58" \o "Agency, 2010 #10224" 58]. In this study Pirfenidone will be administered either by intracarotid or intravenous injection to assess the efficacy and maleficence of Pirfenidone in several mode of administration.

In target cells, Pirfenidone would block nuclear translocation of Smad protein to have TGF-� inhibitory effect  ADDIN EN.CITE  ADDIN EN.CITE.DATA [ HYPERLINK \l "_ENREF_26" \o "Choi, 2012 #14" 26]
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Conclusion
In summary, we propose the rapid proliferation of fibrous ECM producing cells in ischemic core is regulated by endothelium through EndMT. Application of Tie2GFP mice stroke model in this study may reveal the importance of endothelium in this process. We also propose a novel approach of restorative therapy through TGF-� inhibition that may decrease tissue scarring and recruitment of pericytes after ischemic stroke. Hopefully, a better understanding of TGF-� and EndMT process in may provide a better understanding of scarring formation process in ischemic stroke and will give a better restorative therapy for ischemic stroke patients. 



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D<EndNote><Cite><Author>Choi</Author><Year>2012</Year><RecNum>2548</RecNum><DisplayText>[26]</DisplayText><record><rec-number>2548</rec-number><foreign-keys><key app="EN" db-id="wtefz5zpvzae2qe50vrx5dadxeepf5f0rpxe">2548</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Choi, K.</author><author>Lee, K.</author><author>Ryu, S. W.</author><author>Im, M.</author><author>Kook, K. H.</author><author>Choi, C.</author></authors></contributors><auth-address>Department of Bio and Brain Engineering, KAIST, Daejeon, Republic of Korea. ccbioks@kaist.ac.kr</auth-address><titles><title>Pirfenidone inhibits transforming growth factor-beta1-induced fibrogenesis by blocking nuclear translocation of Smads in human retinal pigment epithelial cell line ARPE-19</title><secondary-title>Mol Vis</secondary-title><alt-title>Molecular vision</alt-title></titles><periodical><full-title>Mol Vis</full-title><abbr-1>Molecular vision</abbr-1></periodical><alt-periodical><full-title>Mol Vis</full-title><abbr-1>Molecular vision</abbr-1></alt-periodical><pages>1010-20</pages><volume>18</volume><keywords><keyword>Actins/genetics/metabolism</keyword><keyword>Anti-Inflammatory Agents, Non-Steroidal/*pharmacology</keyword><keyword>Cell Differentiation</keyword><keyword>Cell Line</keyword><keyword>Cell Movement</keyword><keyword>Collagen/genetics/metabolism</keyword><keyword>Epithelial Cells/cytology/*drug effects/metabolism</keyword><keyword>Extracellular Signal-Regulated MAP Kinases/genetics/metabolism</keyword><keyword>Fibroblasts/cytology/metabolism</keyword><keyword>Fibronectins/genetics/metabolism</keyword><keyword>Fibrosis/prevention &amp; control</keyword><keyword>Gene Expression/drug effects</keyword><keyword>Humans</keyword><keyword>JNK Mitogen-Activated Protein Kinases/genetics/metabolism</keyword><keyword>Protein Transport/drug effects</keyword><keyword>Pyridones/*pharmacology</keyword><keyword>Retinal Pigment Epithelium/cytology/*drug effects/metabolism</keyword><keyword>Signal Transduction/drug effects</keyword><keyword>Smad Proteins/genetics/*metabolism</keyword><keyword>Transforming Growth Factor beta1/*antagonists &amp; inhibitors/pharmacology</keyword><keyword>Vitreoretinopathy, Proliferative/drug therapy</keyword></keywords><dates><year>2012</year></dates><isbn>1090-0535 (Electronic)&#xD;1090-0535 (Linking)</isbn><accession-num>22550395</accession-num><urls><related-urls><url>http://www.ncbi.nlm.nih.gov/pubmed/22550395</url></related-urls></urls><custom2>3339036</custom2></record></Cite></EndNote>uD���y������K�
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