Activation of vascular bone morphogenetic protein signaling in diabetes mellitus

Kristina I. Boström, Medet Jumabay, Aleksey Matveyenko, Susanne B. Nicholas, Yucheng Yao

Research output: Contribution to journalArticle

106 Scopus citations

Abstract

RATIONALE: Diabetes mellitus is frequently complicated by cardiovascular disease, such as vascular calcification and endothelial dysfunction, which have been associated with bone morphogenetic proteins (BMPs). OBJECTIVE: To determine whether hyperglycemia in vitro and diabetes in vivo promote vascular BMP activity and correlate with vascular calcification. METHODS AND RESULTS: Increased glucose augmented expression of BMP-2 and BMP-4; the BMP inhibitors matrix Gla protein (MGP) and Noggin; activin-like kinase receptor (ALK)1, -2, -3 and -6; the BMP type 2 receptor; and the vascular endothelial growth factor in human aortic endothelial cells (HAECs). Diabetes induced expression of the same factors in the aortic wall of 3 animal models of diabetes, Ins2 mice, db/db mice, and HIP rats (rats transgenic for human islet amyloid polypeptide), representative of types 1 and 2 diabetes. Conditioned media from glucose-treated HAECs increased angiogenesis in bovine aortic endothelial cells, as mediated by BMP-4, and osteogenesis in calcifying vascular cells, as mediated by BMP-2. BMP-4, MGP, ALK1, and ALK2 were predominantly expressed on the endothelial side of the aorta, and small interfering RNA experiments showed that these genes were regulated as a group. Diabetic mice and rats showed a dramatic increase in aortic BMP activity, as demonstrated by SMAD1/5/8 phosphorylation. This was associated with increased osteogenesis and calcium accumulation. These changes were prevented in the Ins2 mice by breeding them with MGP transgenic mice, which increased aortic BMP inhibition. CONCLUSIONS: Hyperglycemia and diabetes activate vascular BMP activity, which is instrumental in promoting vascular calcification and may be limited by increasing BMP inhibition.

Original languageEnglish (US)
Pages (from-to)446-457
Number of pages12
JournalCirculation research
Volume108
Issue number4
DOIs
StatePublished - Feb 18 2011

Keywords

  • bone morphogenetic protein
  • diabetes mellitus
  • endothelial cells
  • mouse models
  • vascular calcification

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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