Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation.
Excess vascular endothelial growth factor-A disrupts pericyte recruitment during blood vessel formation.
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过量的血管内皮生长因子-A 会破坏血管形成过程中周细胞的募集。
DOI：
10.1007/s10456-018-9648-z
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发表时间：
2019-03
期刊：
影响因子：
9.8
通讯作者：
Chappell JC
中科院分区：
文献类型：
--
作者：
Darden J;Payne LB;Zhao H;Chappell JC
周细胞向新血管中的投资对于血管发育是必不可少的，使得在血管形成的该阶段内的错误调节可促成包括动静脉畸形和脑血管畸形在内的多种病理。因此，阐明血管生成信号通路如何交叉调节周细胞迁移和投资至关重要。在这里，我们破坏了血管内皮生长因子-A（VEGF-A）信号在离体和体外模型的萌芽血管生成，并发现周细胞覆盖受到损害，在VEGF-A扰动。周细胞几乎没有VEGF受体的表达，表明VEGF-A信号转导缺陷直接影响内皮细胞，但间接影响周细胞。小鼠胚胎皮肤离体血管生成的实时成像显示，在暴露于外源性VEGF-A期间，周细胞迁移有限。在VEGF-A功能获得条件下，周细胞和内皮细胞在血小板衍生生长因子-B（PDGF-B）和Notch途径内显示异常转录变化。为了进一步测试周细胞中这些途径之间的潜在串扰，我们用Notch配体Delta样4（Dll 4）和Jagged-1（Jag 1）刺激胚胎周细胞，发现Notch途径活性的诱导，但PDGF受体-β（Pdgfrβ）表达没有变化。相反，PDGFRβ蛋白水平随着VEGF-A活性的错误调节而降低，在对全长PDGFRβ和通过蛋白水解切割或可能通过mRNA剪接产生的截短PDGFRβ亚型的影响中观察到。总体而言，这些观察结果支持这样一种模型，即在血管发育的初始阶段，周细胞分布和覆盖间接受到内皮细胞VEGF-A信号传导和PDGF-B-PDGFRβ动力学下游调节的影响，而在这些早期阶段周细胞Notch信号传导基本上不参与。
Pericyte investment into new blood vessels is essential for vascular development such that mis-regulation within this phase of vessel formation can contribute to numerous pathologies including arteriovenous and cerebrovascular malformations. It is critical therefore to illuminate how angiogenic signaling pathways intersect to regulate pericyte migration and investment. Here, we disrupted vascular endothelial growth factor-A (VEGF-A) signaling in ex vivo and in vitro models of sprouting angiogenesis, and found pericyte coverage to be compromised during VEGF-A perturbations. Pericytes had little to no expression of VEGF receptors, suggesting VEGF-A signaling defects affect endothelial cells directly but pericyte indirectly. Live imaging of ex vivo angiogenesis in mouse embryonic skin revealed limited pericyte migration during exposure to exogenous VEGF-A. During VEGF-A gain-of-function conditions, pericytes and endothelial cells displayed abnormal transcriptional changes within the platelet-derived growth factor-B (PDGF-B) and Notch pathways. To further test potential crosstalk between these pathways in pericytes, we stimulated embryonic pericytes with Notch ligands Delta-like 4 (Dll4) and Jagged-1 (Jag1) and found induction of Notch pathway activity but no changes in PDGF Receptor-β (Pdgfrβ) expression. In contrast, PDGFRβ protein levels decreased with mis-regulated VEGF-A activity, observed in the effects on full-length PDGFRβ and a truncated PDGFRβ isoform generated by proteolytic cleavage or potentially by mRNA splicing. Overall, these observations support a model in which, during the initial stages of vascular development, pericyte distribution and coverage are indirectly affected by endothelial cell VEGF-A signaling and the downstream regulation of PDGF-B-PDGFRβ dynamics, without substantial involvement of pericyte Notch signaling during these early stages.
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