PDGF-Induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 Via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers
Arteriosclerosis, Thrombosis, and Vascular Biology , Volume 32 - Issue 5 p. 1289- 1298
Objective-: In cardiovascular regulation, heme oxygenase-1 (HO-1) activity has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation by promoting cell cycle arrest at the G1/S phase. However, the effect of HO-1 on VSMC migration remains unclear. We aim to elucidate the mechanism by which HO-1 regulates PDGFBB-induced VSMC migration. Methods And Results-: Transduction of HO-1 cDNA adenoviral vector severely impeded human VSMC migration in a scratch, transmembrane, and directional migration assay in response to PDGFBB stimulation. Similarly, HO-1 overexpression in the remodeling process during murine retinal vasculature development attenuated VSMC coverage over the major arterial branches as compared with sham vector-transduced eyes. HO-1 expression in VSMCs significantly upregulated VEGFA and VEGFR2 expression, which subsequently promoted the formation of inactive PDGFRβ/VEGFR2 complexes. This compromised PDGFRβ phosphorylation and impeded the downstream cascade of FAK-p38 signaling. siRNA-mediated silencing of VEGFA or VEGFR2 could reverse the inhibitory effect of HO-1 on VSMC migration. Conclusion-: These findings identify a potent antimigratory function of HO-1 in VSMCs, a mechanism that involves VEGFA and VEGFR2 upregulation, followed by assembly of inactive VEGFR2/PDGFRβ complexes that attenuates effective PDGFRβ signaling.
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|Arteriosclerosis, Thrombosis, and Vascular Biology|
|Organisation||Department of Surgery|
Cheng, C, Haasdijk, R.A, Tempel, D, den Dekker, W.K, Chrifi, I, Blonden, L, … Duckers, H.J. (2012). PDGF-Induced migration of vascular smooth muscle cells is inhibited by heme oxygenase-1 Via VEGFR2 upregulation and subsequent assembly of inactive VEGFR2/PDGFRβ heterodimers. Arteriosclerosis, Thrombosis, and Vascular Biology, 32(5), 1289–1298. doi:10.1161/ATVBAHA.112.245530