Activation of Vascular Smooth Muscle Parathyroid Hormone Receptor Inhibits Wnt/β-Catenin Signaling and Aortic Fibrosis in Diabetic Arteriosclerosis

Abstract

Rationale : Vascular fibrosis and calcification contribute to diabetic arteriosclerosis, impairing Windkessel physiology necessary for distal tissue perfusion. Wnt family members, upregulated in arteries by the low-grade inflammation of “diabesity,” stimulate type I collagen expression and osteogenic mineralization of mesenchymal progenitors via β-catenin. Conversely, parathyroid hormone (PTH) inhibits aortic calcification in low-density lipoprotein receptor (LDLR)-deficient mice fed high fat diabetogenic diets (HFD). Objective : We sought to determine the impact of vascular PTH receptor (PTH1R) activity on arteriosclerotic Wnt/β-catenin signaling in vitro and in vivo. We generated SM-caPTH1R transgenic mice, a model in which the constitutively active PTH1R variant H223R (caPTH1R) is expressed only in the vasculature. Methods and Results : The caPTH1R inhibited Wnt/β-catenin signaling, collagen production, and vascular smooth muscle cell proliferation and calcification in vitro. Transgenic SM-caPTH1R;LDLR +/− mice fed HFD develop diabesity, with no improvements in fasting serum glucose, cholesterol, weight, body composition, or bone mass versus LDLR +/− siblings. SM-caPTH1R downregulated aortic Col1A1 , Runx2 , and Nox1 expression without altering TNF , Msx2 , Wnt7a/b , or Nox4 . The SM-caPTH1R transgene decreased aortic β-catenin protein accumulation and signaling in diabetic LDLR +/− mice. Levels of aortic superoxide (a precursor of peroxide that activates pro–matrix metalloproteinase 9 and osteogenic signaling in vascular smooth muscle cells) were suppressed by the SM-caPTH1R transgene. Aortic calcification, collagen accumulation, and wall thickness were concomitantly reduced, enhancing vessel distensibility. Conclusions : Cell-autonomous vascular smooth muscle cell PTH1R activity inhibits arteriosclerotic Wnt/β-catenin signaling and reduces vascular oxidative stress, thus limiting aortic type I collagen and calcium accrual in diabetic LDLR-deficient mice.