BMP-2 Gene Expression and Effects on Human Vascular Smooth Muscle Cells

Abstract

Bone morphogenetic proteins (BMPs) and their serine/threonine kinase receptors have been identified in atherosclerotic arteries and vascular smooth muscle cells, respectively. Thus, BMPs (the largest subfamily of the TGF-β superfamily) have been implicated in the pathogenesis of atherosclerosis. However, the origins of BMP biosynthesis and the functional roles of BMP in blood vessels are unclear. The present study explored BMP-2 gene expression in various human blood vessels and vascular cell types. Functional in vitro studies were also performed to determine the effects of recombinant human BMP-2 on migration (transwell assay) and proliferation ([³H]-thymidine incorporation) of human aortic vascular smooth muscle cells (HASMC). RT-PCR experiments revealed BMP-2 gene expression in normal and atherosclerotic human arteries as well as cultured human aortic and coronary vascular smooth muscle cells, human umbilical vein endothelial cells (HUVECs) and human macrophages. In cellular migration studies, incubation with BMP-2 produced efficacious (≤610-fold), concentration- and time-dependent chemotaxis of HASMCs (EC₅₀ = 0.8 μM) with little or no effect on HUVEC chemotaxis. The increased HASMC motility induced by BMP-2 was inhibited by coincubation with an anti-BMP-2 mAb. In addition, subthreshold concentrations of BMP-2 produced a dramatic synergistic effect upon platelet-derived growth factor (PDGF)-induced chemotaxis. In contrast to PDGF, BMP-2 had no significant effet on [³H]-thymidine incorporation in HASMC at chemotaxic concentrations (≤6.0 μM) nor did it synergize with the mitogenic effects of PDGF. In conclusion, the expression of BMP-2 by numerous cell types in the blood vessel wall may play a chemotactic or cochemotactic role in the smooth muscle cell response to vascular injury.