DIET-INDUCED DIABETES ACTIVATES AN OSTEOGENIC GENE REGULATORY PROGRAMIN THE AORTAS OF LOW-DENSITY-LIPOPROTEIN RECEPTOR-DEFICIENT MICE

Vascular calcification is common in people with diabetes and its prese nce predicts premature mortality. To clarify the underlying mechanisms , we used low density lipoprotein receptor-deficient (LDLR -/-) mice t o study vascular calcification in the ascending aorta. LDLR -/- mice o n a chow diet did not develop obesity, diabetes, atheroma, or vascular calcification. In contrast, LDLR -/- mice on high fat diets containin g cholesterol developed obesity, severe hyperlipidemia, hyperinsulinem ic diabetes, and aortic atheroma, A high fat diet without cholesterol also induced obesity and diabetes, but caused only moderate hyperlipid emia and did not result in significant aortic atheroma formation. Rega rdless of cholesterol content, high fat diets induced mineralization o f the proximal aorta (assessed by von Kossa staining) and promoted aor tic expression of Msx2 and Msx1, genes encoding homeodomain transcript ion factors that regulate mineralization and osseous differentiation p rograms in the developing skull. Osteopontin (Opn), an osteoblast matr ix protein gene also expressed by activated macrophages, was up-regula ted in the aorta by these high fat diets. In situ hybridization showed that peri-aortic adventitial cells in high fat-fed mice express Msx2. Opn was also detected in this adventitial cell population, but in add ition was expressed by aortic vascular smooth muscle cells and macroph ages of the intimal atheroma, High fat diets associated with hyperinsu linemic diabetes activate an aortic osteoblast transcriptional regulat ory program that is independent of intimal atheroma formation. The spa tial pattern of Msx2 and Opn gene expression strongly suggests that va scular calcification, thought to be limited to the media, is an active process that can originate from an osteoprogenitor cell population in the adventitia.