Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Abstract Only
Publication Acceptance Date: 3/4/2005
Publication Date: 3/4/2005
Citation: Bohnsack, B.L., Lai, L., Hirschi, K.K. 2005. Signaling hierarchy that regulates endothelial cell proliferation and vascular remodeling during vasculogenesis [abstract]. Journal of Federation of American Societies for Experimental Biology Journal. 19(4):A234. Interpretive Summary:
Technical Abstract: We previously demonstrated that during vascular morphogenesis, retinoic acid (RA) is required for the control of endothelial cell proliferation and capillary plexus remodeling. In the present studies, we define the signaling hierarchy downstream of RA that independently regulates these cellular events during vasculogenesis in the yolk sac. We found that while the enzyme required for RA production during early embryogenesis, retinaldehyde dehydrogenase-2 (Raldh2), was expressed in the visceral endoderm, RA receptors a1 and a2 were expressed in endothelial cells in the mesoderm indicating that they are direct targets of RA. In Raldh2-\- embryos, there was downregulation of TGF-b1, fibronectin (Fn) and integrin a5 in endothelial cells, which was associated with decreased visceral endoderm survival and production of soluble effectors VEGF-A, Indian hedgehod (IHH), and bFGF that have receptors on endothelial cells. Exogenous provision of RA or Fn to Raldh2-/- explants in whole mouse embryo culture restored vascular remodeling and visceral endoderm survival, as well as integrin a5 expression and its downstream signaling that controls endothelial growth. Exogenous provision of visceral endoderm-derived factors (VEGF-A, IHH, and bFGF) failed to rescue endothelial cell proliferative control, but collectively promoted vascular remodeling suggesting that these processes are independently regulated via a signaling hierarchy downstream of RA.