A Role for All-Trans-Retinoic Acid in the Early Steps of Lymphatic Vasculature Development

The molecular mechanisms that regulate the earliest steps of
lymphatic vascular system development are unknown. To identify
regulators of lymphatic competence and commitment, we used an in
vitro vascular assay with mouse embryonic stem cell-derived
embryoid bodies (EBs). We found that incubation with retinoic acid
(RA) and, more potently, with RA in combination with cAMP, induced
the expression of the lymphatic competence marker LYVE-1 in the
vascular structures of the EBs. This effect was dependent on RA
receptor (RAR)-alpha and protein kinase A signaling. RA-cAMP
incubation also promoted the development of CD31+/LYVE-1+/Prox1+
cell clusters. In situ studies revealed that RAR-alpha is expressed
by endothelial cells of the cardinal vein in ED 9.5-11.5 mouse
embryos. Timed exposure of mouse and Xenopus embryos to excess of
RA upregulated LYVE-1 and VEGFR-3 on embryonic veins and increased
formation of Prox1-positive lymphatic progenitors. These findings
indicate that RA signaling mediates the earliest steps of lymphatic
vasculature development. Copyright (C) 2010 S. Karger AG, Basel