Osteogenic Regulation of Vascular Calcification

钙化 Wnt信号通路 内科学 内分泌学 骨形态发生蛋白2 骨桥蛋白 人口 生物 细胞生物学 医学 信号转导 生物化学 体外 环境卫生
作者
Dwight A. Towler,JIAN‐SU SHAO,Su‐Li Cheng,Joyce M. Pingsterhaus,Arleen P. Loewy
出处
期刊:Annals of the New York Academy of Sciences [Wiley]
卷期号:1068 (1): 327-333 被引量:99
标识
DOI:10.1196/annals.1346.036
摘要

Abstract: Vascular calcification increasingly afflicts our aging and dysmetabolic population, predisposing patients to cardiovascular mortality and lower extremity amputation. Active osteogenic processes are evident in most histoanatomic variants, including elaboration of BMP2‐Msx2 signals required for craniofacial bone formation. We developed an animal model of diet‐induced diabetes, dyslipidemia, and vascular calcification. High‐fat diets promote vascular calcification in male low‐density lipoprotein receptor (LDLR)‐deficient mice, with concomitant upregulation of aortic BMP2 and Msx2 gene expression. We wished to test if Msx2 exerts pro‐calcific actions during vascular calcification, as it does in craniofacial bone. We studied CMV‐Msx2Tg+;LDLR+ transgenic mice (C57Bl/6), a model previously demonstrated to recapitulate features of Msx2 signaling during craniosynostosis. After 16 weeks of fatty diets, vascular calcification was studied in CMV‐Msx2Tg+ versus nontransgenic sibs. Only CMV‐Msx2Tg+ mice fed high‐fat diets exhibited vascular calcium accumulation by alizarin red staining, noted in the tunica media of coronary arteries and the aorta. Gene expression studies revealed that while Msx2 was expressed primarily in adventitial cells, alkaline phosphatase (ALP) expression and calcification occurred primarily in the tunica media. Msx2 promotes the elaboration of a pro‐osteogenic milieu by upregulating expression of Wingless type (Wnt) ligands while downregulating the canonical antagonist, Dickkopf (Dkk1). Msx2 upregulates aortic Wnt signaling in vivo , revealed by the analysis of TOPGAL+ (Wnt reporter) versus CMV‐Msx2Tg+; TOPGAL+ mice. Aortic Msx2 exerts pro‐osteogenic signaling in vivo and in vitro , mediated in part via the enhancement of paracrine Wnt signaling. Strategies that selectively inhibit aortic Msx2‐Wnt cascades may help diminish the initiation and progression of diabetic vascular disease.
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