首页> 外文期刊>American Journal of Physiology >Apoptosis of pulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth.
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Apoptosis of pulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth.

机译:肺微血管内皮细胞的凋亡刺激血管平滑肌细胞的生长。

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摘要

We have previously hypothesized that the development of severe angioproliferative pulmonary hypertension is associated with not only initial endothelial cell (EC) apoptosis followed by the emergence of apoptosis-resistant proliferating EC but also with proliferation of vascular smooth muscle cells (VSMC). We have demonstrated that EC death results in the selection of an apoptosis-resistant, proliferating, and phenotypically altered EC phenotype. We postulate here that the initial apoptosis of EC induces the release of mediators that cause VSMC proliferation. We cultured EC in an artificial capillary CellMax system designed to simulate the highly efficient functions of the human capillary system. We induced apoptosis of microvascular EC using shear stress and the combined VEGF receptor (VEGFR-1 and -2) inhibitor SU-5416. Flow cytometry for the proliferation marker bromodeoxyuridine showed that serum-free medium conditioned by apoptosed EC induced proliferation of VSMC, whereas serum-free medium conditioned by nonapoptosed EC did not. We also show that medium conditioned by apoptosed EC is characterized by increased concentrations of transforming growth factor (TGF)-beta1 and VEGF compared with medium conditioned by nonapoptosed EC and that TGF-beta1 blockade prevented the proliferation of cultured VSMC. In conclusion, EC death induced by high shear stress and VEGFR blockade leads to the production of factors, in particular TGF-beta1, that activate VSMC proliferation.
机译:我们以前曾假设严重的血管增生性肺动脉高压的发展不仅与最初的内皮细胞(EC)凋亡有关,随后与抗凋亡的增生EC的出现有关,而且与血管平滑肌细胞(VSMC)的增殖有关。我们已经证明EC死亡导致选择抗凋亡,增殖和表型改变的EC表型。我们在这里假设EC的初始凋亡诱导导致VSMC增殖的介质释放。我们在旨在模拟人类毛细管系统高效功能的人工毛细管CellMax系统中培养EC。我们使用剪切应力和联合的VEGF受体(VEGFR-1和-2)抑制剂SU-5416诱导了微血管EC的凋亡。流式细胞仪检测增殖标记物溴脱氧尿苷的结果表明,以凋亡的EC为条件的无血清培养基可诱导VSMC增殖,而以未吸收的EC为条件的无血清培养基则不能。我们还表明,与未凋亡的EC条件化的培养基相比,以凋亡的EC为条件的培养基的特征在于转化生长因子(TGF)-β1和VEGF的浓度增加,并且TGF-β1的阻断阻止了培养的VSMC的增殖。总之,由高剪切应力和VEGFR阻断引起的EC死亡导致激活VSMC增殖的因子特别是TGF-beta1的产生。

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