title: Role of Src in Vascular Hyperpermeability Induced by Advanced Glycation End Products.
abstract: The disruption of microvascular barrier in response to advanced glycation end products (AGEs) stimulation contributes to vasculopathy associated with diabetes mellitus. Here, to study the role of Src and its association with moesin, VE-cadherin and focal adhesion kinase (FAK) in AGE-induced vascular hyperpermeability, we verified that AGE induced phosphorylation of Src, causing increased permeability in HUVECs. Cells over-expressed Src displayed a higher permeability after AGE treatment, accompanied with more obvious F-actin rearrangement. Activation of Src with pcDNA3/flag-Src(Y530F) alone duplicated these effects. Inhibition of Src with siRNA, PP2 or pcDNA3/flag-Src(K298M) abolished these effects. The pulmonary microvascular endothelial cells (PMVECs) isolated from receptor for AGEs (RAGE)-knockout mice decreased the phosphorylation of Src and attenuated the barrier dysfunction after AGE-treatment. In vivo study showed that the exudation of dextran from mesenteric venules was increased in AGE-treated mouse. This was attenuated in RAGE knockout or PP2-pretreated mice. Up-regulation of Src activity induced the phosphorylation of moesin, as well as activation and dissociation of VE-cadherin, while down-regulation of Src abolished these effects. FAK was also proved to interact with Src in HUVECs stimulated with AGEs. Our studies demonstrated that Src plays a critical role in AGE-induced microvascular hyperpermeability by phosphorylating moesin, VE-cadherin, and FAK respectively.
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou 510515, China.
authors.forename: Weijin
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Intensive Care Unit, General Hospital of Guangzhou Military Command, Guangzhou, 510010, China.|Postdoctoral Workstation, Huabo Bio-pharmaceutical Research Institute, Guangzhou 510515, China.
authors.forename: Qiulin
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Weng
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou 510515, China.
authors.forename: Weiju
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou 510515, China.
authors.forename: Qiaobing
authors.initials: Q
authors.lastname: Huang
authors.affiliation: Department of Pathophysiology, Key Laboratory for Shock and Microcirculation Research of Guangdong Province, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Guo
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D055786:Gene Knockout Techniques; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D010766:Phosphorylation; D000067759:Receptor for Advanced Glycation End Products / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D000199:Actins; D015703:Antigens, CD; D015820:Cadherins; D017127:Glycation End Products, Advanced; D008840:Microfilament Proteins; D000067759:Receptor for Advanced Glycation End Products; D019061:src-Family Kinases; D000099152:Cadherin 5; C071058:moesin