Pitavastatin-induced angiogenesis and arteriogenesis is mediated by Notch1 in a murine hindlimb ischemia model without induction of VEGF.
Pitavastatin-induced angiogenesis and arteriogenesis is mediated by Notch1 in a murine hindlimb ischemia model without induction of VEGF.
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DOI：
10.1038/labinvest.2011.5
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发表时间：
2011-05
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影响因子：
--
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中科院分区：
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据报道，Notch信号调节血管生成，与血管内皮生长因子(VEGF)信号相互作用。HMG CoA还原酶抑制剂(他汀类)也改变了血管细胞中的Notch信号，但Notch和VEGF信号在他汀类药物介导的血管生成中的机制和参与尚不清楚。在这里，我们研究了他汀类药物如何激活内皮细胞Notch1，并促进血管生成和动脉生成。我们研究了野生型(WT)和Notch1突变小鼠在接受或不接受匹伐他汀(3 mg/kg/天，P.O.)治疗后肢体缺血后的血流恢复情况。虽然血管内皮生长因子的诱导在缺血肢体中没有改变，但匹伐他汀促进了对照组小鼠缺血肢体的血流恢复，但在Notch1突变小鼠中没有。此外，匹伐他汀可诱导Notch1下游的内皮细胞内皮细胞内皮细胞蛋白B2，并增加WT缺血侧肢体毛细血管和小动脉的密度，但Notch1突变小鼠无此作用。匹伐他汀(100nmol/L)可迅速激活人脐静脉内皮细胞的γ-分泌酶和Notch1，而不需要血管内皮生长因子的诱导，其作用可被药物抑制和AKt基因敲除所抑制。Pitavastatin还促进了Matrigel上的内皮细胞增殖和管状形成，这一作用可被γ分泌酶抑制或Notch1基因敲除所抑制。在Notch1突变的主动脉外植体中，Pitavastatin诱导的微血管萌发也受到损害。综上所述，匹伐他汀通过依赖Akt刺激内皮细胞中的γ分泌酶来激活Notch1，从而在没有血管内皮生长因子诱导的情况下增加血管生成。
Notch signaling is reported to regulate angiogenesis, interacting with vascular endothelial growth factor (VEGF) signaling. HMG CoA reductase inhibitors (statins) also alter Notch signaling in vascular cells, but the mechanism and involvement of Notch and VEGF signaling in statin-mediated angiogenesis remain unclear. Here, we examined how statins activate the endothelial Notch1, and promote angiogenesis and arteriogenesis. We examined blood flow recovery after hindlimb ischemia in wild-type (WT) and Notch1 mutant mice treated with or without pitavastatin (3 mg/kg/day, p.o.). Although VEGF induction was not altered in ischemic limbs, pitavastatin promoted blood flow recovery in ischemic limbs in control mice but not in Notch1 mutant mice. Furthermore, pitavastatin induced endothelial ephrinB2 downstream of Notch1 and increased the density of both capillaries and arterioles in the ischemic limbs of WT but not of Notch1 mutant mice. Pitavastatin (100 nmol/l) rapidly activated γ-secretase and Notch1 in human umbilical vein endothelial cells without VEGF induction, which was suppressed by pharmacological inhibition and knockdown of Akt. Pitavastatin also augmented endothelial proliferation and tube formation on Matrigel, which were suppressed by either γ-secretase inhibition or knockdown of Notch1. Pitavastatin-induced microvascular sprouting was also impaired in Notch1 mutant aortic explants. Taken together, pitavastatin activates Notch1 through Akt-dependent stimulation of γ-secretase in endothelial cells, and thereby increases vasculogenesis without VEGF induction.
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影响因子：
37.8
作者：
Hayashi, S;Asahara, T;Losordo, DW
通讯作者：
Losordo, DW
影响因子：
20.1
作者：
Takeshita, Kyosuke;Satoh, Minoru;Liao, James K.
通讯作者：
Liao, James K.
影响因子：
15.9
作者：
Murohara, T;Asahara, T;Isner, JM
通讯作者：
Isner, JM
影响因子：
64.5
作者：
Benedito, Rui;Roca, Cristina;Adams, Ralf H.
通讯作者：
Adams, Ralf H.
DOI：
10.1073/pnas.0611177104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Suchting, Steven;Freitas, Catarina;Eichmann, Anne
通讯作者：
Eichmann, Anne