title: Beneficial effects of the Src inhibitor, dasatinib, on breakdown of the blood-retinal barrier.
abstract: Src kinase signaling is important in the regulation of microvascular barrier function and endothelial hyperpermeability. This study was designed to evaluate the protective effect of dasatinib, a potent Src inhibitor used clinically for the treatment of cancer, against the breakdown of the blood-retinal barrier (BRB) and the retinal vascular leakage caused by vascular endothelial growth factor (VEGF) and diabetes. We examined the effects of dasatinib on VEGF-induced endothelial hyperpermeability and the loss of vascular endothelial (VE)-cadherin, an endothelial junctional protein. Dasatinib inhibited VEGF-induced phosphorylation of Src in human retinal microvascular endothelial cells (HRMECs). In vitro and in vivo vascular permeability assays showed that dasatinib blocked the VEGF-enhanced hyperpermeability of HRMECs and decreased VEGF-mediated retinal vascular leakage in mice. Immunofluorescent staining of VE-cadherin showed that dasatinib abolished the junctional disappearance of VE-cadherin in VEGF-treated HRMECs and murine retinal vasculature. In addition, we examined the protective effect of dasatinib against diabetes-induced retinal vascular leakage in streptozotocin-induced diabetic rats. An intravitreal injection of dasatinib substantially inhibited the development of hyperpermeable retinal vasculature. Our results indicate that dasatinib is a promising agent for the prevention and treatment of diabetes-induced retinal vascular leakage.
authors.affiliation: College of Pharmacy, Ajou University, Suwon, 16499, Korea.|College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06974, Korea.
authors.forename: So Ra
authors.initials: SR
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06974, Korea. wsuh@cau.ac.kr.
authors.forename: Wonhee
authors.initials: W
authors.lastname: Suh
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001813:Blood-Retinal Barrier / Q000187:drug effects*; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D000069439:Dasatinib / Q000008:administration & dosage / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000378:metabolism; D012171:Retinal Vessels / Q000187:drug effects; D015398:Signal Transduction; D013311:Streptozocin / Q000633:toxicity; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D000069439:Dasatinib; D047428:Protein Kinase Inhibitors; D013311:Streptozocin; D042461:Vascular Endothelial Growth Factor A; D019061:src-Family Kinases; D000099152:Cadherin 5
keywords: Blood retinal barrier; Dasatinib; Diabetes; Leakage