Formation of the collateral circulation is regulated by vascular endothelial growth factor-A and a disintegrin and metalloprotease family members 10 and 17.
Formation of the collateral circulation is regulated by vascular endothelial growth factor-A and a disintegrin and metalloprotease family members 10 and 17.
复制标题
DOI：
10.1161/circresaha.112.279109
复制
发表时间：
2012-12-07
影响因子：
20.1
通讯作者：
Faber JE
中科院分区：
文献类型：
--
作者：
Lucitti JL;Mackey JK;Morrison JC;Haigh JJ;Adams RH;Faber JE
天然(预先存在的)侧支的密度差异很大，是中风、心肌梗死和外周动脉疾病严重程度差异的重要决定因素。然而，人们对健康组织侧支循环形成的机制知之甚少。我们先前发现，血管内皮生长因子表达的变化导致新生小鼠和成年小鼠侧枝密度的差异。在此，我们试图确定胚胎侧枝形成的机制以及血管内皮生长因子在这一过程中的作用。在胚胎13.5天和14.5天之间，软脑膜侧支开始形成，作为现有大脑动脉树小动脉的萌芽状延伸。在胚胎发育过程中，全球高表达的小鼠(VEGFhi/+)形成了更多的侧支，而VEGFlo/+形成了更少的侧支，这与血管构型的差异有关。仅在侧支形成过程中有条件地整体降低VEGF或Flk1显著减少侧支循环的形成，但现在不影响血管构型，并且这种影响在成年后仍然存在。内皮特异性的血管内皮生长因子降低对侧支循环无影响。内皮特异性的去整合素和金属蛋白酶结构域10(ADAM10)的减少和γ分泌酶的抑制增加了侧支的形成，这与它们在血管内皮生长因子诱导的Notch1激活和抑制“促萌发”信号中的作用一致。内皮特异性敲除ADAM17减少侧支形成，与其在内皮细胞迁移和胚胎血管稳定中的作用一致，但不在配体结合的Notch1的激活中。这些影响在成年后也依然存在。软膜侧支的形成发生在一个狭窄的发育窗口，通过萌发的血管生成样机制，需要旁分泌的血管内皮生长因子刺激Flk1-Notch信号，而成体侧支的数量取决于胚胎侧支的形成。
The density of native (pre-existing) collaterals varies widely and is a significant determinant of variation in severity of stroke, myocardial infarction and peripheral artery disease. However, little is known about mechanisms responsible for formation of the collateral circulation in healthy tissues. We previously found that variation in VEGF expression causes differences in collateral density of newborn and adult mice. Herein, we sought to determine mechanisms of collaterogenesis in the embryo and the role of VEGF in this process. Pial collaterals begin forming between embryonic day (E) 13.5 and 14.5 as sprout-like extensions from arterioles of existing cerebral artery trees. Global VEGF-A overexpressing mice (Vegf hi/+) formed more—and Vegf lo/+ formed fewer—collaterals during embryogenesis, in association with differences in vascular patterning. Conditional global reduction of Vegf or Flk1 only during collaterogenesis significantly reduced collateral formation, but now without affecting vascular patterning, and the effects remained in adulthood. Endothelial-specific Vegf reduction had no effect on collaterogenesis. Endothelial-specific reduction of a disintegrin-and-metalloprotease-domain-10 (Adam10) and inhibition of γ-secretase increased collateral formation, consistent with their roles in VEGF-induced Notch1 activation and suppression of “pro-sprouting” signals. Endothelial-specific knockdown of Adam17 reduced collateral formation, consistent with its roles in endothelial cell migration and embryonic vascular stabilization, but not in activation of ligand-bound Notch1. These effects also remained in adulthood. Formation of pial collaterals occurs during a narrow developmental window via a sprouting angiogenesis-like mechanism, requires paracrine VEGF-stimulation of Flk1-Notch signaling, and adult collateral number is dependent on embryonic collaterogenesis.