Activation of vascular bone morphogenetic protein signaling in diabetes mellitus

Circ Res. 2011 Feb 18;108(4):446-57. doi: 10.1161/CIRCRESAHA.110.236596. Epub 2010 Dec 30.

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(Akita/+) 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(Akita/+) 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors / metabolism
  • Animals
  • Aorta / drug effects
  • Aorta / metabolism*
  • Aorta / pathology
  • Bone Morphogenetic Protein 4 / metabolism
  • Bone Morphogenetic Proteins / metabolism*
  • Calcinosis / metabolism
  • Calcinosis / physiopathology
  • Calcium-Binding Proteins / metabolism
  • Carrier Proteins / metabolism
  • Cells, Cultured
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / physiopathology
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Disease Models, Animal
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / pathology
  • Extracellular Matrix Proteins / metabolism
  • Glucose / pharmacology
  • Humans
  • Hyperglycemia / metabolism
  • Hyperglycemia / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Osteogenesis / physiology
  • Rats
  • Rats, Transgenic
  • Signal Transduction / physiology*
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • Calcium-Binding Proteins
  • Carrier Proteins
  • Extracellular Matrix Proteins
  • Vascular Endothelial Growth Factor A
  • matrix Gla protein
  • noggin protein
  • Activin Receptors
  • Glucose