Abstract
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
Substances
-
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