Ji Yeon Kim1, Jun-Sub Choi1, Sun-Hwa Song1, Ji-Eun Im1, Jung-Mo Kim1, Kyungjong Kim1, Soonboem Kwon1, Hwa Kyoung Shin1, Choun-Ki Joo1, Byung Ho Lee1, Wonhee Suh2. 1. From the College of Pharmacy, Ajou University, Suwon, Korea (J.Y.K., S.-H.S., J.-E.I., K.K., S.K., W.S.); Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (J.-S.C., C.-K.J.); Department of Molecular and Life Science, CHA University, Seoul, Korea (J.-M.K.); Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Gyeongnam, Korea (H.K.S.); and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Korea (B.H.L.). 2. From the College of Pharmacy, Ajou University, Suwon, Korea (J.Y.K., S.-H.S., J.-E.I., K.K., S.K., W.S.); Department of Ophthalmology and Visual Science, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea (J.-S.C., C.-K.J.); Department of Molecular and Life Science, CHA University, Seoul, Korea (J.-M.K.); Division of Meridian and Structural Medicine, School of Korean Medicine, Pusan National University, Gyeongnam, Korea (H.K.S.); and Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon, Korea (B.H.L.). wsuh@ajou.ac.kr.
Abstract
OBJECTIVE: Although stem cell factor (SCF) has been shown to play a critical role in hematopoiesis, gametogenesis, and melanogenesis, the function of SCF in the regulation of vascular integrity has not been studied. APPROACH AND RESULTS: We demonstrated that SCF binds to and activates the cKit receptor in endothelial cells, thereby increasing the internalization of vascular endothelial-cadherin and enhancing extravasation of dyes to a similar extent as vascular endothelial growth factor. SCF-mediated cKit activation in endothelial cells enhanced the phosphorylation of endothelial nitric oxide (NO) synthase via the phosphoinositide 3-kinase/Akt signaling pathway and subsequently increased the production of NO. Inhibition of endothelial NO synthase expression and NO synthesis using small interfering RNA knockdown and chemical inhibitors substantially diminished the ability of SCF to increase the internalization of vascular endothelial-cadherin and in vitro endothelial permeability. SCF-induced increase in extravasation of the dyes was abrogated in endothelial NO synthase knockout mice, which indicates that endothelial NO synthase-mediated NO production was responsible for the SCF-induced vascular leakage. Furthermore, we demonstrated that the expression of SCF and cKit was significantly higher in the retina of streptozotocin-injected diabetic mice than in the nondiabetic control animals. Depletion of SCF by intravitreous injection of anti-SCF-neutralizing immunoglobulin G significantly prevented vascular hyperpermeability in the retinas of streptozotocin-injected diabetic mice. CONCLUSIONS: Our data reveal that SCF disrupts the endothelial adherens junction and enhances vascular leakage, as well as suggest that anti-SCF/cKit therapy may hold promise as a potential therapy for the treatment of hyperpermeable vascular diseases.
OBJECTIVE: Although stem cell factor (SCF) has been shown to play a critical role in hematopoiesis, gametogenesis, and melanogenesis, the function of SCF in the regulation of vascular integrity has not been studied. APPROACH AND RESULTS: We demonstrated that SCF binds to and activates the cKit receptor in endothelial cells, thereby increasing the internalization of vascular endothelial-cadherin and enhancing extravasation of dyes to a similar extent as vascular endothelial growth factor. SCF-mediated cKit activation in endothelial cells enhanced the phosphorylation of endothelial nitric oxide (NO) synthase via the phosphoinositide 3-kinase/Akt signaling pathway and subsequently increased the production of NO. Inhibition of endothelial NO synthase expression and NO synthesis using small interfering RNA knockdown and chemical inhibitors substantially diminished the ability of SCF to increase the internalization of vascular endothelial-cadherin and in vitro endothelial permeability. SCF-induced increase in extravasation of the dyes was abrogated in endothelial NO synthase knockout mice, which indicates that endothelial NO synthase-mediated NO production was responsible for the SCF-induced vascular leakage. Furthermore, we demonstrated that the expression of SCF and cKit was significantly higher in the retina of streptozotocin-injected diabeticmice than in the nondiabetic control animals. Depletion of SCF by intravitreous injection of anti-SCF-neutralizing immunoglobulin G significantly prevented vascular hyperpermeability in the retinas of streptozotocin-injected diabeticmice. CONCLUSIONS: Our data reveal that SCF disrupts the endothelial adherens junction and enhances vascular leakage, as well as suggest that anti-SCF/cKit therapy may hold promise as a potential therapy for the treatment of hyperpermeable vascular diseases.
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