Osteogenic regulation of vascular calcification

Dwight A. Towler, Jian Su Shao, Su Li Cheng, Joyce M. Pingsterhaus, Arleen P. Loewy

Research output: Contribution to journalArticle

73 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)327-333
Number of pages7
JournalAnnals of the New York Academy of Sciences
Volume1068
Issue number1
DOIs
StatePublished - Apr 2006

Keywords

  • Adventitia
  • Alkaline phosphatase
  • Calcium
  • Diabetes BMP2
  • Dkk1
  • Msx2
  • Myofibroblast
  • Osteoblast
  • Osterix
  • PTH/PTHrP receptor
  • Tunica media
  • Wnt
  • β-catenin

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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  • Cite this

    Towler, D. A., Shao, J. S., Cheng, S. L., Pingsterhaus, J. M., & Loewy, A. P. (2006). Osteogenic regulation of vascular calcification. Annals of the New York Academy of Sciences, 1068(1), 327-333. https://doi.org/10.1196/annals.1346.036