Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis
Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis
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DOI：
10.1101/gad.242002
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发表时间：
2002-10-15
影响因子：
10.5
通讯作者：
Shima, DT
中科院分区：
文献类型：
--
作者：
Ruhrberg, C;Gerhardt, H;Shima, DT
哺乳动物肺和果蝇气管的分支形态发生依赖于上皮生长分泌调节剂的精确定位来选择分支位置和直接分支延伸，但控制血管分支的细胞间信号先前尚未被确定。我们发现VEGF（120/120）小鼠胚胎，经过工程改造，仅表达缺乏肝素结合的VEGF- a亚型，因此缺乏细胞外基质相互作用域，毛细血管分支形成特异性减少。这种缺陷不是由刺激内皮细胞增殖的异构体特异性差异引起的，也不是由通过Nrp1受体的异构体特异性信号传导受损引起的。相反，肝素结合突变胚胎中VEGF-A细胞外定位的变化导致内皮细胞在生长血管中的分布发生改变。新生内皮细胞不是被招募到其他分支中，而是优先整合到现有血管中，以增加管腔直径。正常VEGF-A浓度梯度的破坏也损害了内皮细胞丝状伪足的定向延伸，这表明肝素结合VEGF-A同种异构体通常提供空间受限的刺激信号，使其极化，从而引导发芽的内皮细胞启动血管分支的形成。与这一观点一致，我们在胚胎中发现了相反的缺陷，仅含有VEGF-A的肝素结合异构体，包括过多的内皮丝状伪足和异位部位异常薄的血管分支。我们得出结论，VEGF-A异构体在细胞外空间的差异定位为调节血管分支模式提供了一个控制点。
Branching morphogenesis in the mammalian lung and Drosophila trachea relies on the precise localization of secreted modulators of epithelial growth to select branch sites and direct branch elongation, but the intercellular signals that control blood vessel branching have not been previously identified. We found that VEGF(120/120) mouse embryos, engineered to express solely an isoform of VEGF-A that lacks heparin-binding, and therefore extracellular matrix interaction domains, exhibited a specific decrease in capillary branch formation. This defect was not caused by isoform-specific differences in stimulating endothelial cell proliferation or by impaired isoform-specific signaling through the Nrp1 receptor. Rather, changes in the extracellular localization of VEGF-A in heparin-binding mutant embryos resulted in an altered distribution of endothelial cells within the growing vasculature. Instead of being recruited into additional branches, nascent endothelial cells were preferentially integrated within existing vessels to increase lumen caliber. The disruption of the normal VEGF-A concentration gradient also impaired the directed extension of endothelial cell filopodia, suggesting that heparin-binding VEGF-A isoforms normally provide spatially restricted stimulatory cues that polarize and thereby guide sprouting endothelial cells to initiate vascular branch formation. Consistent with this idea, we found opposing defects in embryos harboring only a heparin-binding isoform of VEGF-A, including excess endothelial filopodia and abnormally thin vessel branches in ectopic sites. We conclude that differential VEGF-A isoform localization in the extracellular space provides a control point for regulating vascular branching pattern.