Endothelial progenitor cells may inhibit apoptosis of pulmonary microvascular endothelial cells: new insights into cell therapy for pulmonary arterial hypertension
Endothelial progenitor cells may inhibit apoptosis of pulmonary microvascular endothelial cells: new insights into cell therapy for pulmonary arterial hypertension
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内皮祖细胞可能抑制肺微血管内皮细胞凋亡：肺动脉高压细胞治疗的新见解
DOI：
10.1080/14653240902960460
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发表时间：
2009-01-01
期刊：
影响因子：
4.5
通讯作者：
Wang, Xing-Xiang
中科院分区：
文献类型：
--
作者：
Xia, Liang;Fu, Guo-Sheng;Wang, Xing-Xiang
背景目的内皮细胞凋亡是肺动脉高压（PAH）的病理生理基础.内皮祖细胞（EPC）释放的一些因子/细胞因子已被发现是有效的细胞凋亡抑制剂。本研究的目的是探讨EPC对肺微血管内皮细胞（PMVEC）存活的影响与PAH condition.MethodsPMVEC凋亡诱导高剪切应力（HSS）与血清饥饿或促炎因子在人工毛细血管系统。结果EPC条件培养液（CM）能显著抑制HSS和血清饥饿条件下PMVEC的凋亡。血管内皮生长因子（VEGF）-A或-B阻断可使其减弱。EPC CM促进PMVEC增殖，VEGF-A或IL-8阻断可减弱其增殖。EPC-CM可减少HSS加促炎因子诱导的PMVEC凋亡。EPC CM的抗凋亡作用通过阻断血管内皮生长因子受体（VEGFR）-1或-2而减弱。然而，促增殖作用似乎仅通过VEGFR-2阻断而减弱。EPCCM可增强Erk 1/2和Akt的磷酸化。VEGFR-2阻断导致Erk 1/2和Akt活化的显著抑制; VEGFR-1阻断仅导致Erk 1/2活化。人源性VEGF与EPC共定位于肺小动脉，EPC移植导致caspase-3表达下调。结论VEGF-A/B-VEGFR-1/2-Erk 1/2信号通路是EPC抗PMVEC凋亡的主要途径，VEGF-A-VEGFR-2-Akt信号通路是EPC促增殖的主要途径。移植的EPC以旁分泌方式分泌的生长因子抑制PAH肺中的细胞凋亡。
Background aimsEndothelial apoptosis underlies the pathophysiology of pulmonary arterial hypertension (PAH). Some factors/cytokines released by endothelial progenitor cells (EPC) have been revealed as potent inhibitors of apoptosis. The aim of this study was to investigate the effects of EPC on pulmonary microvascular endothelial cell (PMVEC) survival with the PAH condition.MethodsPMVEC apoptosis was induced by high shear stress (HSS) with serum starvation or pro-inflammatory factors in an artificial capillary system. EPC were delivered into monocrotaline-induced PAH nude rats.ResultsPMVEC apoptosis under HSS and serum starvation conditions was significantly inhibited by EPC conditioned medium (CM). It was attenuated by vascular endothelial growth factor (VEGF)-A or -B blocking. EPC CM promoted PMVEC proliferation, which was weakened by VEGF-A or interleukin (IL)-8 blocking. The EPC CM caused less apoptosis of PMVEC induced by HSS plus pro-inflammatory factors. The anti-apoptotic effect of EPC CM was attenuated by blockade of either vascular endothelial growth factor receptor (VEGFR)-1 or -2. However, the pro-proliferating effect appeared to be weakened only by VEGFR-2 blocking. Both Erk1/2 and Akt phosphorylation were enhanced by EPC CM. VEGFR-2 blockage led to significant inhibition of Erk1/2 and Akt activation; VEGFR-1 blockage only of Erk1/2 activation. Human-origin VEGF co-localized with incorporated EPC in small pulmonary arterioles, and EPC transplantation resulted in down-regulation of caspase-3 expression.ConclusionsThe VEGF-A/B-VEGFR-1/2-Erk1/2 signal pathway took major responsibility for the anti-apoptotic effects of EPC on PMVEC, and VEGF-A-VEGFR-2-Akt for pro-proliferating effects. Growth factors, secreted in a paracrine manner by transplanted EPC, inhibited cell apoptosis in PAH lung.