Abstract 3715: Bone Morphogenetic Protein-2 Plays Crucial Roles In The Formation Of Medial Calcification And Atherosclerosis In Vivo
Vascular calcification is one of the most important risk factor for the cardiovascular diseases. There are two types of vascular calcification; 1) medial calcification associated with diabetes and aging 2) intimal calcification associated with atherosclerosis. Recently, bone formation regulatory factors have been suggested to play unique roles in the formation of vascular calcification. Here, we investigated the potential role of de-differentiated VSMC (dediff-VSMC) in the intimal calcification in vitro, as well as the effect of bone morphogenetic protein (BMP)-2 on vascular calcification in vivo. We prepared re-differentiated (rediff-VSMC) and de-differentiated VSMC (dediff-VSMC) in vitro, and analyzed expression of bone formation regulatory factors. BMP-2, a potent initiator for osteoblastic differentiation, significantly increased in dediff-VSMC while its inhibitors noggin and chordin decreased comparing to rediff-VSMC. In contrast, anti-calcification factors such as MGP and ENPP-1 were all downregurated in dediff-VSMC. These results suggest that enhanced BMP-2 signaling as well as reduced anti-calcification factors may play unique roles in the formation of intimal calcification. Since it remains unclear whether BMP-2 plays a role in the vascular calcification in vivo, we generated BMP-2 transgenic mouse using αSMA-promoter. When calcitriol was administered, BMP-2-Tg mouse showed significant medial calcification with appearance of osteoblast-like cells in the calcified vessel wall whereas no calcification was observed in wild-type mouse. We then generated BMP-2-Tg mouse using ApoE-knockout mouse, and fed them with high fat diet. Even in BMP-2-Tg/ApoE-KO mice, significant intimal calcification of atherosclerotic legion was not observed. However, BMP-2-Tg/ApoE-KO mice demonstrated significantly less atherosclerotic legion comparing to ApoE-KO mice. These results suggest that BMP-2 has inhibitory effect on the formation of atherosclerosis, and this effect may exceed its pro-calcification function in the atherosclerotic intima. Our data define the distinct function of BMP-2 in the vascular diseases; 1) pro-calcification factor for medial calcification, and 2) inhibitory factor for atherosclerosis.