Abstract 236: Shaping Waves of BMP Inhibition During Vasculogenesis

Abstract

During early embryogenesis, gradients of bone morphogenetic proteins (BMPs) have been shown to be critical in controlling patterning and growth of developing tissues. Two members of the BMP family are well known as strong modulators of vascular development, BMP4 and BMP9. Hereditary hemorrhagic telangiectasia 2 (HHT2) is caused by mutations in a BMP receptor, the activin receptor-like kinase 1 (Alk1) gene, and characterized by abnormal vascular networks and arteriovenous malformations (AVMs). ALK1 expression and signaling are tightly regulated by BMP4 and 9 and their respective inhibitors, matrix Gla protein (MGP) and Crossveinless-2 (CV2), through negative feedback regulation. Aberrant ALK1 signaling disrupting endothelial cell (EC) differentiation is closely related to vascular morphogenesis and AVMs, and depends on normal action of MGP and CV2. We have previously shown that deletion of the Mgp gene leads to AVMs in multiple organs (100% penetrance), characterized by large-caliber shunts and abnormal endothelium with increased cellularity and EC marker expression. Using in vitro , in silico and in vivo approaches, we found that the vascular growth, patterning and EC maturation are orchestrated by “shaping waves” resembling those in somatogenesis. In cultures ECs, the waves are seen as temporal oscillations of MGP and CV2 expression in response to BMP9, whereas in tissue such as the retina, the waves are observed as stripes perpendicular to the direction of growth. Thus, lack of MGP or disruptions in BMP9/ALK1/Endoglin signaling, as in HHT, will cause alterations in the expression of the BMP inhibitors and the patterning during vascular development.