Marino Daniela, Dabouras Vasilios, Brändli André W, Detmar Michael
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland.
J Vasc Res. 2011;48(3):236-51. doi: 10.1159/000320620. Epub 2010 Nov 23.
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)-α 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-α 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.
调节淋巴血管系统发育最早阶段的分子机制尚不清楚。为了鉴定淋巴能力和定向分化的调节因子，我们使用了一种体外血管分析方法，该方法利用小鼠胚胎干细胞衍生的胚状体（EBs）。我们发现，用视黄酸（RA）孵育，更有效的是将RA与cAMP联合孵育，可诱导EBs血管结构中淋巴能力标志物LYVE-1的表达。这种效应依赖于视黄酸受体（RAR）-α和蛋白激酶A信号传导。RA-cAMP孵育还促进了CD31+/LYVE-1+/Prox1+细胞簇的发育。原位研究表明，在胚胎发育第9.5-11.5天的小鼠胚胎中，主静脉内皮细胞表达RAR-α。对小鼠和非洲爪蟾胚胎定时给予过量RA，可上调胚胎静脉上的LYVE-1和VEGFR-3，并增加Prox1阳性淋巴祖细胞的形成。这些发现表明，RA信号传导介导了淋巴血管系统发育的最早阶段。
