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First published online 19 November 2003
doi: 10.1242/dev.00887
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,
1 Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030,
USA
2 Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX
77030, USA
3 Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX
77030, USA
4 Department of Molecular and Cellular Biology, Baylor College of Medicine,
Houston, TX 77030, USA
5 Department of Medicine, Baylor College of Medicine, Houston, TX 77030,
USA
6 Center for Cardiovascular Development, Baylor College of Medicine, Houston, TX
77030, USA
Author for correspondence (e-mail:
khirschi{at}bcm.tmc.edu)
Accepted 22 September 2003
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.
Key words: Vascular development, Retinoic acid, Endothelial cell cycle control, Mouse
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