Critical role of endothelial Notch1 signaling in postnatal angiogenesis
Critical role of endothelial Notch1 signaling in postnatal angiogenesis
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DOI：
10.1161/01.res.0000254788.47304.6e
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发表时间：
2007-01-05
影响因子：
20.1
通讯作者：
Liao, James K.
中科院分区：
文献类型：
--
作者：
Takeshita, Kyosuke;Satoh, Minoru;Liao, James K.
Notch受体是胚胎发生过程中细胞命运的重要介质，但它们在成人生理学，特别是在出生后血管生成中的作用仍然未知。在Notch受体中，只有Notch 1和Notch 4在血管内皮细胞中表达。在这里，我们发现，与野生型小鼠相比，单倍不足的整体或内皮特异性Notch 1（+/-）小鼠，但不是Notch 4（-/-）小鼠，后肢缺血的血流恢复和出生后的新血管形成受损。缺血时血管内皮生长因子（VEGF）的表达在野生型和Notch突变小鼠之间是相当的，这表明Notch 1是VEGF信号的下游。用VEGF处理内皮细胞可增加早老素蛋白水解加工、γ-分泌酶活性、Notch 1切割和Hes-1（分裂同源物1的多毛增强子）表达，所有这些都可通过用磷脂酰肌醇3-激酶/蛋白激酶Akt抑制剂处理内皮细胞或用显性阴性Akt突变体感染内皮细胞来阻断。事实上，抑制γ-分泌酶活性导致血管生成减少，并抑制VEGF诱导的内皮细胞增殖、迁移和存活。Notch 1活性胞间结构域的过表达挽救了γ-分泌酶抑制剂对VEGF诱导的血管生成的抑制作用。这些发现表明，磷脂酰肌醇3-激酶/Akt途径介导的γ-分泌酶和Notch 1激活VEGF和Notch 1是VEGF诱导的出生后血管生成的关键。这些结果表明，Notch 1可能是一个新的治疗靶点，用于改善缺血肢体的血管生成反应和血流恢复。
Notch receptors are important mediators of cell fate during embryogenesis, but their role in adult physiology, particularly in postnatal angiogenesis, remains unknown. Of the Notch receptors, only Notch1 and Notch4 are expressed in vascular endothelial cells. Here we show that blood flow recovery and postnatal neovascularization in response to hindlimb ischemia in haploinsufficient global or endothelial-specific Notch1(+/-) mice, but not Notch4(-/-) mice, were impaired compared with wild-type mice. The expression of vascular endothelial growth factor (VEGF) in response to ischemia was comparable between wild-type and Notch mutant mice, suggesting that Notch1 is downstream of VEGF signaling. Treatment of endothelial cells with VEGF increases presenilin proteolytic processing, gamma-secretase activity, Notch1 cleavage, and Hes-1 (hairy enhancer of split homolog-1) expression, all of which were blocked by treating endothelial cells with inhibitors of phosphatidylinositol 3-kinase/protein kinase Akt or infecting endothelial cells with a dominant-negative Akt mutant. Indeed, inhibition of gamma-secretase activity leads to decreased angiogenesis and inhibits VEGF-induced endothelial cell proliferation, migration, and survival. Overexpression of the active Notch1 intercellular domain rescued the inhibitory effects of gamma-secretase inhibitors on VEGF-induced angiogenesis. These findings indicate that the phosphatidylinositol 3-kinase/Akt pathway mediates gamma-secretase and Notch1 activation by VEGF and that Notch1 is critical for VEGF-induced postnatal angiogenesis. These results suggest that Notch1 may be a novel therapeutic target for improving angiogenic response and blood flow recovery in ischemic limbs.