Activation of vascular smooth muscle parathyroid hormone receptor inhibits Wnt/β-catenin signaling and aortic fibrosis in diabetic arteriosclerosis

Su Li Cheng, Jian Su Shao, Linda R. Halstead, Kathryn Distelhorst, Oscar Sierra, Dwight A. Towler

Research output: Contribution to journalArticle

71 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)271-282
Number of pages12
JournalCirculation Research
Volume107
Issue number2
DOIs
StatePublished - Jul 23 2010

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Parathyroid Hormone Receptor Type 1
Catenins
Arteriosclerosis
LDL Receptors
Vascular Smooth Muscle
Fibrosis
Smooth Muscle Myocytes
High Fat Diet
Collagen Type I
Transgenes
Blood Vessels
Collagen
Vascular Calcification
Peroxides
Body Composition
Parathyroid Hormone
Superoxides
Transgenic Mice
Siblings
Fasting

Keywords

  • β-catenin
  • arteriosclerosis
  • diabetes
  • parathyroid hormone
  • Wnt

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Activation of vascular smooth muscle parathyroid hormone receptor inhibits Wnt/β-catenin signaling and aortic fibrosis in diabetic arteriosclerosis. / Cheng, Su Li; Shao, Jian Su; Halstead, Linda R.; Distelhorst, Kathryn; Sierra, Oscar; Towler, Dwight A.

In: Circulation Research, Vol. 107, No. 2, 23.07.2010, p. 271-282.

Research output: Contribution to journalArticle

Cheng, Su Li ; Shao, Jian Su ; Halstead, Linda R. ; Distelhorst, Kathryn ; Sierra, Oscar ; Towler, Dwight A. / Activation of vascular smooth muscle parathyroid hormone receptor inhibits Wnt/β-catenin signaling and aortic fibrosis in diabetic arteriosclerosis. In: Circulation Research. 2010 ; Vol. 107, No. 2. pp. 271-282.
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AU - Shao, Jian Su

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AU - Distelhorst, Kathryn

AU - Sierra, Oscar

AU - Towler, Dwight A.

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AB - 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.

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