Sonic hedgehog induces capillary morphogenesis by endothelial cells through phosphoinositide 3-kinase
Sonic hedgehog induces capillary morphogenesis by endothelial cells through phosphoinositide 3-kinase
复制标题
DOI：
10.1074/jbc.m210635200
复制
发表时间：
2003-03-07
影响因子：
4.8
通讯作者：
Kanetake, H
中科院分区：
文献类型：
--
作者：
Kanda, S;Mochizuki, Y;Kanetake, H
Sonic hedgehog（Shh）在许多细胞类型中充当形态发生剂。最近的研究表明，刺猬信号参与血管发育以及出生后的血管生成。然而，Shh对培养的内皮细胞的直接作用尚未清楚地显示。为了解决这个问题，我们研究了Shh对小鼠脑毛细血管内皮细胞（IBE细胞）和人脐静脉内皮细胞（HLTVEC）形态学变化的影响。Shh通过这些细胞诱导毛细血管形态发生。环巴胺或百日咳毒素可抑制该作用。磷脂酰肌醇3-激酶（PI 3-kinase）抑制剂LY 294002也能阻断Shh诱导的毛细血管形态发生。Shh迅速增加了IBE细胞和HLTVEC中的PI 3-激酶活性;环巴胺可抑制该活性。在Shh处理的IBE细胞中，Gli 1的核定位增加，这不受LY 294002的影响。放线菌素D和放线菌酮抑制Shh诱导的毛细血管形态发生。在表达激酶失活的c-Fes的IBE细胞中，Shh未能刺激PI 3激酶活性和毛细血管形态发生。综合考虑，Shh通过快速激活c-Fes/PI 3-激酶途径和转录调节途径诱导内皮细胞毛细血管形态发生。
Sonic hedgehog (Shh) acts as a morphogen in many cell types. Recent studies have shown that hedgehog signaling is involved in vascular development as well as postnatal angiogenesis. However, the direct action of Shh on cultured endothelial cells has not been clearly shown. To address this issue, we examined the effect of Shh on morphological changes by murine brain capillary endothelial cells (IBE cells) and human umbilical endothelial cells (HLTVECs). Shh induced capillary morphogenesis by these cells. The effect was inhibited by cyclopamine or pertussis toxin. Shh-induced capillary morphogenesis was also blocked by LY294002, a phosphoinositide 3-kinase (PI3-kinase) inhibitor. Shh rapidly increased PI3-kinase activity in IBE cells and HLTVECs; this activity was inhibited by cyclopamine. Nuclear localization of Gli1 was increased in Shh-treated IBE cells, which was not affected by LY294002. Actinomycin D and cycloheximide inhibited Shh-induced capillary morphogenesis. In IBE cells expressing kinase-inactive c-Fes, Shh failed to stimulate PI3-kinase activity and capillary morphogenesis. Considered collectively, Shh induced capillary morphogenesis of endothelial cells through both rapid activation of c-Fes/PI3-kinase pathways and transcriptionally regulated pathways.