Endothelial cell migration during murine yolk sac vascular remodeling occurs by means of a Rac1 and FAK activation pathway in vivo.
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.
Enciso
Josephine M
JM
Division of Neonatology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, California, USA. jenciso@mednet.ucla.edu
Konecny
Christine M
CM
Karpen
Heidi E
HE
Hirschi
Karen K
KK
D000445:Aldehyde Oxidoreductases / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D016596:Vinculin / Q000235:genetics / Q000378:metabolism; D015017:Yolk Sac / Q000166:cytology*; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D016596:Vinculin; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D020830:rac1 GTP-Binding Protein