1. 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.
- Author
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Cheng C, Haasdijk RA, Tempel D, den Dekker WK, Chrifi I, Blonden LA, van de Kamp EH, de Boer M, Bürgisser PE, Noorderloos A, Rens JA, ten Hagen TL, and Duckers HJ
- Subjects
- Cell Movement, Cell Proliferation, Heme Oxygenase-1 metabolism, Humans, Muscle, Smooth, Vascular cytology, Muscle, Smooth, Vascular drug effects, Platelet-Derived Growth Factor pharmacology, Signal Transduction, Vascular Endothelial Growth Factor Receptor-2 biosynthesis, Heme Oxygenase-1 pharmacology, Muscle, Smooth, Vascular metabolism, Platelet-Derived Growth Factor metabolism, RNA, Messenger genetics, Receptor, Platelet-Derived Growth Factor beta metabolism, Up-Regulation drug effects, Vascular Endothelial Growth Factor Receptor-2 genetics
- Abstract
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., Conclusions: 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.
- Published
- 2012
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