title: Signaling hierarchy downstream of retinoic acid that independently regulates vascular remodeling and endothelial cell proliferation.
abstract: We previously demonstrated that during vascular morphogenesis, retinoic acid (RA) is required for the control of endothelial cell proliferation and capillary plexus remodeling. Herein, we investigate the mechanisms by which RA regulates these processes in the yolk sac. We found that although the enzyme required for RA production during early embryogenesis, retinaldehyde dehydrogenase-2 (Raldh2), was expressed in the visceral endoderm, RA receptors alpha1 and alpha2 were expressed in endothelial cells in the mesoderm, indicating that they are direct targets of RA. In Raldh2(-/-) embryos, there was down-regulation of TGF-beta1, fibronectin (Fn) and integrin alpha5, which was associated with decreased visceral endoderm survival and production of VEGF-A, Indian hedgehog (IHH), and bFGF. Exogenous provision of RA or Fn to Raldh2(-/-) explants in whole mouse embryo culture restored vascular remodeling, visceral endoderm survival, as well as integrin alpha5 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.
authors.affiliation: Department of Molecular and Cellular Biology, Children's Nutrition Research Center, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas 77030, USA.
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Bohnsack
authors.forename: Lihua
authors.initials: L
authors.lastname: Lai
authors.forename: Pascal
authors.initials: P
authors.lastname: Dolle
authors.forename: Karen K
authors.initials: KK
authors.lastname: Hirschi
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000196:embryology / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism; D004707:Endoderm / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D039564:Integrin alphaV / Q000378:metabolism; D008648:Mesoderm; D051379:Mice; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014781:Viscera / Q000196:embryology; D015017:Yolk Sac / Q000378:metabolism
chemical_list: D005353:Fibronectins; D053823:Hedgehog Proteins; D039564:Integrin alphaV; C508961:Tgfb1 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse; D020928:Mitogen-Activated Protein Kinases