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Rationale Vascular calcification is a regulated process that involves osteoprogenitor cells and frequently complicates common vascular disease such as atherosclerosis and diabetic vasculopathy. However, it is not clear if the vascular endothelium has a role in contributing osteoprogenitor cells to the calcific lesions. Objective To determine if the vascular endothelium contributes osteoprogenitor cells to vascular calcification. Methods and Results In this study, we use two mouse models of vascular calcification, mice with gene deletion of matrix Gla protein (MGP), a BMP-inhibitor, and Ins2Akita/+ mice, a diabetes model. We show that enhanced bone morphogenetic protein (BMP) signaling in both types of mice stimulates the vascular endothelium to contribute osteoprogenitor cells to the vascular calcification. The enhanced BMP signaling results in endothelial-mesenchymal transitions and the emergence of multipotent cells, followed by osteoinduction. Endothelial markers co-localize with multipotent and osteogenic markers in calcified arteries by immunostaining and fluorescence-activated cell sorting. Lineage tracing using Tie2-Gfp transgenic mice supports an endothelial origin of the osteogenic cells. Enhancement of MGP expression in Ins2Akita/+ mice, as mediated by an Mgp transgene limits the generation of multipotent cells. Moreover, MGP-depleted human aortic endothelial cells in vitro acquire multipotency rendering the cells susceptible to osteoinduction by BMP and high glucose. Conclusions Our data suggest that the endothelium is a source of osteoprogenitor cells in vascular calcification that occurs in disorders with high BMP activation such as deficiency of BMP inhibitors and diabetes.

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