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

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-med...