Submitted to: Development
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/22/2003
Publication Date: 12/1/2003
Citation: Lai, L., Bohnsack, B.L., Niederreither, K., Hirschi, K.K. 2003. Retinoic acid regulates endothelial cell proliferation during vasculogenesis. Development. 130(26):6465-6474. Interpretive Summary: Vitamin A is known to be important for the maintenance of human health, but its role in blood vessel growth is not well understood. Our study examined the role of retinoic acid, a metabolite of vitamin A, in mammalian blood vessel formation. By studying embryonic blood vessel development in genetically altered retinoic acid-deficient mice, we found that retinoic acid is crucial in controlling blood vessel cell proliferation and is important for vascular development.
Technical Abstract: A dietary deficiency of vitamin A is associated with cardiovascular abnormalities in avian and murine systems. Retinoic acid (RA) is the active metabolite of vitamin A and whether it directly regulates mammalian blood vessel formation has not been determined and is investigated herein. We used mice rendered RA-deficient via targeted deletion of retinaldehyde dehydrogenase 2 (Raldh2(-/-)), the enzyme required to produce active RA in the embryo. Histological examination at E8.0-8.5, prior to cardiac function and systemic blood circulation, revealed that capillary plexi formed in Raldh2(-/-) yolk sacs and embryos, but were dilated, and not appropriately remodeled or patterned. Raldh2(-/-) endothelial cells exhibited significantly increased expression of phosphohistone 3 and decreased expression of p21 and p27, suggesting that RA is required to control endothelial cell cycle progression during early vascular development. Uncontrolled endothelial cell growth, in Raldh2(-/-) mutants, was associated with decreased endothelial cell maturation, disrupted vascular plexus remodeling and lack of later stages of vessel assembly, including mural cell differentiation. Maternally administrated RA restored endothelial cell cycle control and vascular patterning. Thus, these data indicate that RA plays a crucial role in mammalian vascular development; it is required to control endothelial cell proliferation and vascular remodeling during vasculogenesis.