The Role of Thrombospondin-1 in Hypoxia-induced Migration of Human Vascular Smooth Muscle Cells

Abstract

When the arterial wall thickens and blood-diffusion capacity is low in atherosclerotic lesions, hypoxia is a key factor for the development of atherosclerosis. Under hypoxic conditions, >100 genes, including those encoding many growth factors, are known to be induced by a transcriptional factor, hypoxia-inducible factor-1alpha (HIF-1alpha). In this study, to examine whether HIF-1alpha-dependent induction of growth factors is associated with the proliferation and migration of vascular cells in atherosclerotic lesions, we studied the role of thrombospondin-1 (TSP-1), which is induced by hypoxia, in the pathogenesis and progression of atherosclerosis in human coronary artery smooth muscle cells (CASMCs). Under hypoxic conditions, expression of HIF-1alpha increased time-dependently in human CASMCs with a concomitant increase in the proliferation and migration of cells. Under these conditions, the mRNA and protein levels of TSP-1 and the mRNA level of TSP-1 receptor, integrin beta3, were also enhanced. Neutralizing antibody against TSP-1 reduced hypoxia-induced migration, but not proliferation. Similarly, RGD peptide, which binds to integrin beta3, inhibited cell migration under hypoxia. In HIF-1alpha-knockdown CASMCs, in which expression of HIF-1alpha and TSP-1 mRNA and proteins is suppressed, hypoxia-induced migration was markedly reduced. In conclusion, hypoxia in atherosclerotic lesions induces TSP-1, which plays important roles in acceleration of the migration of human CASMCs and the progression of atherosclerosis.