Affiliation:
1. From the Department of Medicine, Washington University, St Louis, Mo.
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine,Physiology
Cited by
90 articles.
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