DDR1: a novel regulator of intimal calcification

Abstract

Intimal calcification is a serious complication of advanced atherosclerotic disease. Low density lipoprotein receptor‐deficient mice (Ldlr−/−) fed a high fat diet develop complicated atherosclerotic lesions. Here we report that Ldlr−/−mice develop foci of intimal calcification in the aortic arch, which are positive for Alizarin Red S (AR) and Von Kossa (VK), two histological stains for mineralized tissues. Cells within these foci are surrounded by a type II collagen‐rich matrix and express a chondrocyte‐specific transcription factor, Sox‐9. Atherosclerotic lesions are rich in collagens, which have been shown to promote smooth muscle cell‐mediated calcification. Thus, we hypothesized a role for the discoidin domain receptor 1 (DDR1), a collagen receptor, in intimal calcification. Male mice with a combined deficiency in LDLR and DDR1 (Ldlr−/−;Ddr1−/−) and controls (Ldlr−/−;Ddr1+/+) were fed a high fat diet for 12 weeks. DDR1‐deficiency attenuated the incidence of intimal calcification, measured by positive staining for AR and VK. Aortic arch calcium extraction confirmed a reduction in the extent of calcification in the Ldlr−/−;Ddr1−/− mice compared with control mice (45 ± 22 vs 123 ± 52 μmol/g dry weight). This study demonstrates regions of calcification within the intimal lesions of Ldlr−/− mice fed an atherogenic diet and provides novel evidence of a role for DDR1 in this process.