|ENCISO, JOSEPHINE - University Of California|
|KONECNY, CHRISTINE - Baylor College Of Medicine|
|KARPEN, HEIDI - Baylor College Of Medicine|
|HIRSCHI, KAREN - Children'S Nutrition Research Center (CNRC)|
Submitted to: Developmental Dynamics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/11/2010
Publication Date: 8/24/2010
Citation: Enciso, J.M., Konecny, C.M., Karpen, H.E., Hirschi, K.K. 2010. Endothelial cell migration during murine yolk sac vascular remodeling occurs by means of a Rac1 and FAK activation pathway in vivo. Developmental Dynamics. 239(10):2570-2583.
Interpretive Summary: The process which controls cell migration as blood vessels begin to form in the body are largely unidentified at the molecular level; these experiments attempt to explain some of those mechanisms. By using mice, which did not have a protein (Raldh2), which helps to produce retinoic acid, this paper specifically showed that retinoic acid is essential to vascular remodeling in an embryo’s yolk sac because it is not normal when it’s missing. In those same mice, a cytoskeletal protein (vinculin) associated with cell-cell and cell-matrix junctions was increased in the yolk sacs, and molecular events important for focal adhesion turnover were decreased. If retinoic acid was provided to mice that could not make it themselves, vascular remodeling was rescued and appeared normal. The results provide new evidence about the regulation of endothelial cell migration as blood vessels begin to form and remodel in the body.
Technical Abstract: The molecular mechanism(s) controlling cell migration during vascular morphogenesis in vivo remain largely undefined. To address this within a physiological context, we used retinaldehyde dehydrogenase-2 (Raldh2) null mouse embryos and demonstrate that retinoic acid (RA) deficiency results in abnormal yolk sac vascular remodeling due to decreased Rac1 activation, increased RhoA activation, and increased focal adhesions. Vinculin was increased in Raldh2-/- yolk sacs, and molecular events important for focal adhesion turnover, FAK phosphorylation (Tyr397) and FAK-paxillin association, were decreased. RA-rescue of vascular remodeling down-regulated vinculin and restored FAK phosphorylation (Tyr397) and FAK-paxillin association. Furthermore, vascular rescue with vascular endothelial growth factor-A, Indian hedgehog, and basic fibroblast growth factor restored FAK phosphorylation (Tyr397) in the endothelium of Raldh2-/- yolk sacs. Our results provide new insights into the regulation of endothelial cell migration during vascular remodeling in vivo by adding the Rac1 and FAK activation pathway as a critical mediator of focal adhesion formation and turnover during vascular remodeling.