title: A potential role for caveolin-1 in VEGF-induced fibronectin upregulation in mesangial cells: involvement of VEGFR2 and Src.
abstract: VEGF is known to be an endothelial cell mitogen that stimulates angiogenesis by promoting endothelial cell survival, proliferation, migration, and differentiation. Recent studies have suggested that VEGF may play a pivotal role in glomerular sclerosis through extracellular matrix protein (ECM) accumulation, although the signaling mechanism is still unclear. The GTPase RhoA has been implicated in VEGF-induced type IV collagen accumulation in some settings. Here we study the role of different VEGF receptors and membrane microdomain caveolae in VEGF-induced RhoA activation and fibronectin upregulation in mesangial cells (MCs). In primary rat MC, VEGF time and dose dependently increased fibronectin production. Rho pathway inhibition blocked VEGF-induced fibronectin upregulation. VEGF-induced RhoA activation was prevented by disrupting caveolae with cholesterol depletion and rescued by cholesterol repletion. VEGF stimulation led to a markedly increased VEGFR2/caveolin-1 but failed to increase VEGFR1/caveolin-1 association. VEGF also increased caveolin-1/Src association and activated Src, and Src inhibitor blocked RhoA activation and fibronectin upregulation. Src-mediated phosphorylation of caveolin-1 on Y14 has also been implicated in signaling responses. Overexpression of nonphosphorylatable caveolin-1 Y14A prevented VEGF-induced RhoA activation and fibronectin upregulation. In vivo, although VEGFR1 and VEGFR2 protein levels were both increased in the kidney cortices of diabetic rats, VEGFR2/caveolin-1 association but not VEGFR1/caveolin-1 association was significantly increased. In conclusion, VEGF-induced RhoA activation and fibronectin upregulation require caveolae and caveolin-1 interaction with VEGFR2 and Src. Interference with caveolin/-ae signaling may provide new avenues for the treatment of fibrotic renal disease.
authors.affiliation: Department of Biochemistry, Wuhan University School of Basic Medical Sciences, Wuhan, Hubei, People's Republic of China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Wu
authors.forename: Baifang
authors.initials: B
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Ye
authors.forename: Zeling
authors.initials: Z
authors.lastname: Xiao
mesh_terms: D000818:Animals; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism*; D002478:Cells, Cultured; D005353:Fibronectins / Q000378:metabolism*; D008297:Male; D050527:Mesangial Cells / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D005353:Fibronectins; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D040301:Vascular Endothelial Growth Factor Receptor-2; D019061:src-Family Kinases; D020742:rhoA GTP-Binding Protein