Vascular fibrosis and calcification contribute to diabetic arteriosclerosis, impairing distal tissue perfusion. Ldlr knockout mice serve as a model for this arterial calcification. Males fed a high fat Western diet develop obesity, diabetes, hyperinsulinemia, hypertriglyceridemia and hypercholesterolemia with progressively severe arterial calcification. Wnt (wingless-related MMTV) gene family members, up-regulated in arteries by the low-grade inflammation of "diabesity", stimulate type I collagen expression and osteogenic mineralization of mesenchymal progenitors via β-catenin (Ctnnb1, catenin (cadherin associated protein), beta 1). Conversely, parathyroid hormone (PTH) inhibits aortic calcification in LDLR (low density lipoprotein receptor)-deficient mice fed high fat diabetogenic diets (HFD).
This compound mutant strain expresses the constitutively active H223R mutant form of Pth1r (parathyroid hormone 1 receptor) under the regulatory control of the vascular smooth muscle-specific mouse SM22 (Tagln, transgelin) promoter as well as a knockout of the Ldlr gene. It was constructed to determine the impact of vascular PTHR1 activity on arteriosclerotic Wnt/β-catenin signaling.
This strain demonstrates that cell-autonomous vascular smooth muscle cell PTHR1 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.
