Abstract 12244: Paracrine Osteogenic Signals Via Bone Morphogenetic Protein-2 Accelerate Atherosclerotic Intimal Calcification
Vascular calcification is an important risk factor for cardiovascular diseases. Recent findings suggest that bone calcification regulatory factors, locally expressed in blood vessels, actively regulate the formation of vascular calcification. However, detailed molecular mechanisms underlying the atherosclerotic intimal calcification remain unclear. Here, we investigated a potential role of dedifferentiated VSMCs in the formation of atherosclerotic intimal calcification. In vitro studies revealed that bone morphogenetic protein-2 (BMP-2), a potent initiator for osteoblastic differentiation was markedly up-regulated in dedifferentiated VSMCs in conjunction with the down-regulation of endogenous BMP-2 inhibitors such as noggin, chordin and MGP. Moreover, conditioned medium from dedifferentiated VSMCs but not from redifferentiated VSMCs stimulated osteoblastic differentiation of mesenchymal progenitor C2C12 cells, which was completely abolished by BMP-2 knockdown. These results suggest that paracrine osteogenic signals via BMP-2 are substantially enhanced in dedifferentiated VSMCs. We therefore generated BMP-2 transgenic mice in which BMP-2 expression was driven by αSMA-promoter, and mated them with ApoE-knockout mice to obtain BMP-2-Tg/ApoE-KO mice. After 30 weeks with high cholesterol diet, serum lipid concentrations and the size of atherosclerotic lesion were not different between ApoE-KO and BMP-2-Tg/ApoE-KO mice. Nevertheless, atherosclerotic intimal calcification, assessed by alizarin red-S and von Kossa staining, was significantly greater in BMP-2-Tg/ApoE-KO than in ApoE-KO mice. Osteoblast-like cells expressing ALP are significantly increased in atherosclerotic intima in BMP-2-Tg/ApoE-KO mice, indicating that BMP-2 secreted by VSMCs accelerated the osteoblastic differentiation in atherosclerotic intima in vivo. In conclusion, we demonstrated an important role of dedifferentiated-VSMCs in the pathophysiology of atherosclerotic calcification through activating paracrine BMP-2 osteogenic signals. Inhibition of VSMC-dedifferentiation could be an ideal therapeutic target for the treatment of atherosclerosis.
- © 2010 by American Heart Association, Inc.