Differential regulation of blood flow-induced neovascularization and mural cell recruitment by vascular endothelial growth factor and angiopoietin signalling.
Differential regulation of blood flow-induced neovascularization and mural cell recruitment by vascular endothelial growth factor and angiopoietin signalling.
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DOI：
10.1113/jp273430
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发表时间：
2017-03-01
期刊：
影响因子：
--
通讯作者：
Bates DO
中科院分区：
文献类型：
--
作者：
Stone OA;Carter JG;Lin PC;Paleolog E;Machado MJ;Bates DO
将一氧化氮(NO)介导的血流量增加与血管生成素-1-Tie2受体信号相结合，在生理性血管生成模型中诱导动脉粥样硬化--从毛细血管形成小动脉。这种NO-Tie介导的动脉粥样硬化需要内源性血管内皮生长因子(VEGF)信号。抑制血管内皮生长因子信号可增加微血管中周细胞的覆盖率。综上所述，这些发现表明，功能性新生血管的产生需要密切的NO-Tie2信号的滴定和局部的VEGF诱导，这表明使用外源性VEGF表达作为治疗新生血管的方法可能不成功。血管生成素通过血管内皮生长因子(VEGF)受体和带有Ig G和EGF结构域-2(Tie2)受体的酪氨酸激酶(Tie2)，与血流结合，形成功能性血管网络。我们通过比较一氧化氮(NO)介导的血管扩张诱导的肠系膜新生微血管的表型，以及可溶性Tie2(STie2)抑制血管生成素信号转导和可溶性FMS样酪氨酸激酶受体1(SFlt1)抑制血管生成素信号转导成熟大鼠肠系膜脂肪垫(SFlt1)诱导新生血管的表型，验证了血管内皮生长因子和血管生成素1(Ang1)在一氧化氮(NO)介导的血管扩张诱导的新生血管形成中的不同作用。我们发现，用sFlt1抑制血管内皮生长因子(使功能性血管面积增加881%±998%，增加279%±72%)和用sTie2抑制血管生成素(抑制血管生成素，使血管面积增加337%±667%)，可以阻断NO介导的血管生成。在血流增强的情况下，需要外源性血管生成素-1来诱导动脉粥样硬化(8.6%±71.3%的血管有血管平滑肌细胞的募集)。STie2和sFlt1均抑制VSMC募集(均为0%)，而抑制VEGF可增加周细胞向新生血管的募集(从27%±0.2%增加到54%±0.3%)。我们证明，血管内皮生长因子和血管生成素信号的良好平衡是形成功能性血管网络所必需的。内源性血管内皮生长因子信号可防止新生血管周细胞过度覆盖，并在一氧化氮介导的血管扩张和血管生成素信号(NO-Tie介导的动脉生成)增加的过程中对VSMC募集是必需的。因此，治疗性血管重塑范例可能需要调节血流的治疗，以利用内源性血管内皮生长因子和外源性血管紧张素转换酶1，以有效地新生血管。将一氧化氮(NO)介导的血流量增加与血管生成素-1-Tie2受体信号相结合，在生理性血管生成模型中诱导动脉粥样硬化--从毛细血管形成小动脉。这种NO-Tie介导的动脉粥样硬化需要内源性血管内皮生长因子(VEGF)信号。抑制血管内皮生长因子信号可增加微血管中周细胞的覆盖率。综上所述，这些发现表明，功能性新生血管的产生需要密切的NO-Tie2信号的滴定和局部的VEGF诱导，这表明使用外源性VEGF表达作为治疗新生血管的方法可能不成功。
Combining nitric oxide (NO)‐mediated increased blood flow with angiopoietin‐1–Tie2 receptor signalling induces arteriolargenesis – the formation of arterioles from capillaries – in a model of physiological angiogenesis. This NO–Tie‐mediated arteriolargenesis requires endogenous vascular endothelial growth factor (VEGF) signalling. Inhibition of VEGF signalling increases pericyte coverage in microvessels. Together these findings indicate that generation of functional neovasculature requires close titration of NO–Tie2 signalling and localized VEGF induction, suggesting that the use of exogenous VEGF expression as a therapeutic for neovascularization may not be successful. Signalling through vascular endothelial growth factor (VEGF) receptors and the tyrosine kinase with IgG and EGF domains‐2 (Tie2) receptor by angiopoietins is required in combination with blood flow for the formation of a functional vascular network. We tested the hypothesis that VEGF and angiopoietin‐1 (Ang1) contribute differentially to neovascularization induced by nitric oxide (NO)‐mediated vasodilatation, by comparing the phenotype of new microvessels in the mesentery during induction of vascular remodelling by over‐expression of endothelial nitric oxide synthase in the fat pad of the adult rat mesentery during inhibition of angiopoietin signalling with soluble Tie2 (sTie2) and VEGF signalling with soluble Fms‐like tyrosine kinase receptor‐1 (sFlt1). We found that NO‐mediated angiogenesis was blocked by inhibition of VEGF with sFlt1 (from 881 ± 98% increase in functional vessel area to 279 ± 72%) and by inhibition of angiopoietin with sTie2 (to 337 ± 67%). Exogenous angiopoietin‐1 was required to induce arteriolargenesis (8.6 ± 1.3% of vessels with recruitment of vascular smooth muscle cells; VSMCs) in the presence of enhanced flow. sTie2 and sFlt1 both inhibited VSMC recruitment (both 0%), and VEGF inhibition increased pericyte recruitment to newly formed vessels (from 27 ± 2 to 54 ± 3% pericyte ensheathment). We demonstrate that a fine balance of VEGF and angiopoietin signalling is required for the formation of a functional vascular network. Endogenous VEGF signalling prevents excess neovessel pericyte coverage, and is required for VSMC recruitment during increased nitric oxide‐mediated vasodilatation and angiopoietin signalling (NO–Tie‐mediated arteriogenesis). Therapeutic vascular remodelling paradigms may therefore require treatments that modulate blood flow to utilize endogenous VEGF, in combination with exogenous Ang1, for effective neovascularization. Combining nitric oxide (NO)‐mediated increased blood flow with angiopoietin‐1–Tie2 receptor signalling induces arteriolargenesis – the formation of arterioles from capillaries – in a model of physiological angiogenesis. This NO–Tie‐mediated arteriolargenesis requires endogenous vascular endothelial growth factor (VEGF) signalling. Inhibition of VEGF signalling increases pericyte coverage in microvessels. Together these findings indicate that generation of functional neovasculature requires close titration of NO–Tie2 signalling and localized VEGF induction, suggesting that the use of exogenous VEGF expression as a therapeutic for neovascularization may not be successful.