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

Abstract

Primary human aorta-derived VSMC (Lonza, Breda, NL) were cultured on gelatin-coated plates at 37°C/5% CO 2 in SmGM-2 medium 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 PDGFR/VEGFR2 complexes. This compromised PDGFR 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/PDGFR complexes that attenuates effective PDGFR signaling. (Arterioscler Thromb Vasc Biol . 2012;32:1289-1298 .) PdGF-induced Migration of Vascular smooth

Age-dependent expression of VEGFR2 in deep brain arteries in small vessel disease, CADASIL, and healthy brains

“…VEGFR2 has also been observed within VSMC, in small arteries of human spinal cord [6] and in blood vessels of peripheral tissues [8,36,37].…”

“…Our data do not support association with blood vessel density, or small vessel disease. Within experimental systems, the potent tyrosine kinase-linked VEGFR2 has functional effects on migration, differentiation state and functional phenotype of VSMC [7,8,22,36,37,43]. In human aortic VSMC cultures, and in adult mouse retina, VEGFR2 had a potent anti-migratory effect, mediated by VEGFR2-PDGFRβ receptor complexes [8].…”

“…Within experimental systems, the potent tyrosine kinase-linked VEGFR2 has functional effects on migration, differentiation state and functional phenotype of VSMC [7,8,22,36,37,43]. In human aortic VSMC cultures, and in adult mouse retina, VEGFR2 had a potent anti-migratory effect, mediated by VEGFR2-PDGFRβ receptor complexes [8]. In transgenic mice (VEGF δ/δ ) lacking physiological levels of VEGF expression, arterial VSMC lacked mature contractile phenotype, and their sympathetic neuro-effector junctions were abnormal in structure and function [37].…”

“…Activation of VEGFR2 in endothelial cells by the canonical ligand VEGF is associated with angiogenesis and increased vascular permeability. Within CNS tissues VEGFR2 has been reported in neurones [4,6,24,27,39], oligodendrocyte progenitors [19], microglial cells [12] and in VSMC within spinal cord [6] and retinal arteries [8]. The ligand VEGF is also expressed in brain tissue [3,23,38].…”

The apolipoprotein A‐I mimetic peptide, D‐4F, restrains neointimal formation through heme oxygenase‐1 up‐regulation

“…This inducible enzyme is implicated in the cellular defences against oxidative stress, inflammation and apoptosis associated with atherosclerosis 34, 35. HO‐1 inhibits VSMC proliferation and migration in vitro and reduces intimal hyperplasia during vascular injury in vivo 36, 37. Wu et al .…”