Stem cell factor is a potent endothelial permeability factor.
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.


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.
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.).
Ji Yeon
JY
Kim
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.).
Jun-Sub
JS
Choi
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.).
Sun-Hwa
SH
Song
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.).
Ji-Eun
JE
Im
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.).
Jung-Mo
JM
Kim
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.).
Kyungjong
K
Kim
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.).
Soonboem
S
Kwon
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.).
Hwa Kyoung
HK
Shin
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.).
Choun-Ki
CK
Joo
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.).
Byung Ho
BH
Lee
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.
Wonhee
W
Suh
D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D042783:Endothelial Cells / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D034622:RNA Interference; D012171:Retinal Vessels / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
D057134:Antibodies, Neutralizing; D019089:Stem Cell Factor; D009569:Nitric Oxide; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D058539:Phosphatidylinositol 3-Kinase; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt
nitric oxide synthase type III; stem cell factor; vascular permeability