Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium

Blood. 2012 May 24;119(21):5037-47. doi: 10.1182/blood-2011-10-385906. Epub 2012 Apr 3.


The importance of morphogenetic proteins (BMPs) and their antagonists in vascular development is increasingly being recognized. BMP-4 is essential for angiogenesis and is antagonized by matrix Gla protein (MGP) and crossveinless 2 (CV2), both induced by the activin receptor like-kinase 1 (ALK1) when stimulated by BMP-9. In this study, however, we show that CV2 preferentially binds and inhibits BMP-9 thereby providing strong feedback inhibition for BMP-9/ALK1 signaling rather than for BMP-4/ALK2 signaling. CV2 disrupts complex formation involving ALK2, ALK1, BMP-4, and BMP-9 required for the induction of both BMP antagonists. It also limits VEGF expression, proliferation, and tube formation in ALK1-expressing endothelial cells. In vivo, CV2 deficiency translates into a dysregulation of vascular BMP signaling, resulting in an abnormal endothelium with increased endothelial cellularity and expression of lineage markers for mature endothelial cells. Thus, mutual regulation by BMP-9 and CV2 is essential in regulating the development of the vascular endothelium.

Publication types

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

MeSH terms

  • Activin Receptors, Type I / antagonists & inhibitors
  • Activin Receptors, Type I / metabolism
  • Activin Receptors, Type II / antagonists & inhibitors
  • Activin Receptors, Type II / metabolism
  • Animals
  • Bone Morphogenetic Protein 4 / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Carrier Proteins / physiology*
  • Cattle
  • Cells, Cultured
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiology
  • Gene Expression Regulation / drug effects
  • Growth Differentiation Factor 2 / antagonists & inhibitors*
  • Growth Differentiation Factor 2 / metabolism*
  • Growth Differentiation Factor 2 / pharmacology
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Protein Binding / drug effects
  • Substrate Specificity


  • BMP4 protein, human
  • BMPER protein, human
  • Bone Morphogenetic Protein 4
  • Carrier Proteins
  • Growth Differentiation Factor 2
  • ACVR1 protein, human
  • ACVRL1 protein, human
  • Activin Receptors, Type I
  • Activin Receptors, Type II