Division of Cardiovascular Medicine, Department of Medicine, Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Dev Biol. 2010 Nov 15;347(2):325-36. doi: 10.1016/j.ydbio.2010.08.030. Epub 2010 Sep 15.
Heart valve malformations are one of the most common types of birth defects, illustrating the complex nature of valve development. Vascular endothelial growth factor (VEGF) signaling is one pathway implicated in valve formation, however its specific spatial and temporal roles remain poorly defined. To decipher these contributions, we use two inducible dominant negative approaches in mice to disrupt VEGF signaling at different stages of embryogenesis. At an early step in valve development, VEGF signals are required for the full transformation of endocardial cells to mesenchymal cells (EMT) at the outflow tract (OFT) but not atrioventricular canal (AVC) endocardial cushions. This role likely involves signaling mediated by VEGF receptor 1 (VEGFR1), which is highly expressed in early cushion endocardium before becoming downregulated after EMT. In contrast, VEGFR2 does not exhibit robust cushion endocardium expression until after EMT is complete. At this point, VEGF signaling acts through VEGFR2 to direct the morphogenesis of the AVC cushions into mature, elongated valve leaflets. This latter role of VEGF requires the VEGF-modulating microRNA, miR-126. Thus, VEGF roles in the developing valves are dynamic, transitioning from a differentiation role directed by VEGFR1 in the OFT to a morphogenetic role through VEGFR2 primarily in the AVC-derived valves.
心脏瓣膜畸形是最常见的先天性缺陷之一，这表明瓣膜发育的复杂性。血管内皮生长因子（VEGF）信号通路是参与瓣膜形成的途径之一，但它的具体时空作用仍未被明确界定。为了解密这些贡献，我们使用两种在小鼠中诱导的显性负性方法，在胚胎发生的不同阶段干扰 VEGF 信号通路。在瓣膜发育的早期，VEGF 信号对于流出道（OFT）心内膜细胞向间质细胞（EMT）的完全转化是必需的，但在房室管（AVC）心内膜垫中则不是必需的。这一作用可能涉及由 VEGFR1 介导的信号通路，该信号通路在早期心内膜垫中高度表达，在 EMT 后下调。相比之下，VEGFR2 在 EMT 完成后才开始在心脏垫中大量表达。此时，VEGF 信号通过 VEGFR2 作用，将 AVC 心内膜垫的形态发生引导为成熟的、长的瓣膜小叶。VEGF 的后一种作用需要 VEGF 调节的 microRNA，miR-126。因此，VEGF 在发育中的瓣膜中的作用是动态的，从 OFT 中由 VEGFR1 指导的分化作用过渡到主要在 AVC 衍生的瓣膜中通过 VEGFR2 发挥的形态发生作用。
