Retinoic acid regulates endothelial cell proliferation during vasculogenesis
Retinoic acid regulates endothelial cell proliferation during vasculogenesis
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DOI：
10.1242/dev.00887
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发表时间：
2003-12-01
期刊：
影响因子：
4.6
通讯作者：
Hirschi, KK
中科院分区：
文献类型：
--
作者：
Lai, LH;Bohnsack, BL;Hirschi, KK
饮食中维生素A的缺乏与禽类和小鼠系统的心血管异常有关。维甲酸(RA)是维生素A的活性代谢物，它是否直接调节哺乳动物的血管形成尚未确定，本文对此进行了研究。我们使用了通过靶向缺失视黄醛脱氢酶2(Raldh2(-/-))而导致RA缺陷的小鼠，Raldh2(-/-)是在胚胎中产生活性RA所需的酶。E8.0-8.5的组织学检查显示，在心功能和全身血液循环之前，Raldh2(-/-)卵黄囊和胚胎中形成了毛细血管丛，但扩张，没有适当的重塑或图案。Raldh2(-/-)内皮细胞磷酸组蛋白3表达显著增加，p21和p27表达降低，提示RA在血管发育早期需要控制内皮细胞周期进程。在Raldh2(-/-)突变体中，内皮细胞生长失控与内皮细胞成熟度降低、血管丛重建中断以及缺乏包括壁细胞分化在内的血管组装的后期阶段有关。母体服用维甲酸可恢复内皮细胞周期控制和血管构型。因此，这些数据表明，RA在哺乳动物血管发育中起着至关重要的作用；在血管形成过程中，它是控制内皮细胞增殖和血管重塑所必需的。
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.