Expression of mutant BMPR-II in pulmonary endothelial cells promotes apoptosis and a release of factors that stimulate proliferation of pulmonary arterial smooth muscle cells.
Expression of mutant BMPR-II in pulmonary endothelial cells promotes apoptosis and a release of factors that stimulate proliferation of pulmonary arterial smooth muscle cells.
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DOI：
10.4103/2045-8932.78100
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发表时间：
2011-01
影响因子：
2.6
通讯作者：
Morrell NW
中科院分区：
文献类型：
--
作者：
Yang X;Long L;Reynolds PN;Morrell NW
骨形态发生蛋白II受体基因(BMPR-II)突变是遗传性肺动脉高压(PAH)的主要原因。尽管血管内皮细胞和血管内皮细胞BMPR-II功能障碍已被认为与体内的肺动脉高压有关，但BMPR-II突变对这两种重要细胞之间相互作用的影响却知之甚少。我们使用腺病毒载体在人肺动脉内皮细胞(PAECs)中过表达野生型或突变型(D485G)BMPR-II。转导突变BMPR-II基因的PAECs对细胞凋亡的敏感性增加。与野生型BMPR-II转染的PAECs条件培养液相比，转导突变BMPR-II的PAECs条件培养液可促进PASMCs的增殖。与野生型BMPR-II转染组细胞相比，转染型BMPR-II组的PAEC在条件培养液中分泌更多的转化生长因子-β-1和FGF2。在转化生长因子β生物测定中，表达突变BMPR-II的PAEC的条件培养液也显示了荧光素酶活性的增强。表达突变型BMPR-II的PASMC在条件培养液中的增殖可被转化生长因子-β1抗体、小分子ALK5(SD208)或FGFR1SU5402所抑制。我们的结论是，BMPR-II突变增加了PAECs对凋亡的易感性，并导致刺激PASMCs增殖的生长因子的分泌。这些过程可能有助于观察到家族性或遗传性PAH患者的肺动脉重塑。
Mutations in the bone morphogenetic protein type II receptor gene (BMPR-II) are the major cause of heritable pulmonary arterial hypertension (PAH). Although both endothelial and smooth muscle cell BMPR-II dysfunction have been seen to contribute to pulmonary hypertension in vivo, little is known about the impact of BMPR-II mutation on the interaction between these two important cell types. We employed adenoviral vectors to overexpress wild type or mutant (kinase-deficient mutation, D485G) BMPR-II in human pulmonary arterial endothelial cells (PAECs). PAECs transfected with mutant BMPR-II demonstrated increased susceptibility to apoptosis. Conditioned media from PAECs transfected with mutant BMPR-II increased the proliferation of pulmonary arterial smooth muscle cells (PASMCs), when compared with conditioned media from PAECs transfected with wild-type BMPR-II. PAECs transfected with mutant BMPR-II released higher levels of TGF-β1 and FGF2 into the conditioned media than the wild-type BMPR-II-transfected cells. Conditioned media from PAECs expressing mutant BMPR-II also showed increased activation of luciferase activity in a TGF-β bioassay. The increased proliferation observed in PASMCs exposed to conditioned media from PAECs expressing mutant BMPR-II was inhibited by neutralizing the antibodies to TGF-β1, or small molecule inhibitors of ALK-5 (SD208) or FGFR1 (SU5402). We conclude that mutation in BMPR-II increases susceptibility to apoptosis of PAECs and leads to secretion of growth factors that stimulate the proliferation of PASMCs. These processes may contribute to the remodeling of pulmonary arteries observed in patients with familial or heritable PAH.