Dominant negative mutation of the TGF-β receptor blocks hypoxia-induced pulmonary vascular remodeling
Dominant negative mutation of the TGF-β receptor blocks hypoxia-induced pulmonary vascular remodeling
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DOI：
10.1152/japplphysiol.00595.2005
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发表时间：
2006-02-01
影响因子：
3.3
通讯作者：
Oparil, S
中科院分区：
文献类型：
--
作者：
Chen, YF;Feng, JA;Oparil, S
本研究利用表达转化生长因子（TGF）-β II 型受体的诱导性显性失活突变的新型转基因小鼠模型（DnTGF β RII 小鼠）来检验 TGF-β 信号在慢性缺氧诱导的肺动脉压升高以及血管和肺泡重塑的发病机制中发挥重要作用的假设。将 9 至 10 周龄的雄性 DnTGF beta RII 和对照非转基因 (NTG) 小鼠暴露于常压缺氧 (10% O-2) 或空气中 6 周。在低氧暴露前 1 周开始饮用 25 mM ZnSO4 水诱导 DnTGF beta RII 的表达。与 NTG 对照组相比，DnTGF beta RII 小鼠中缺氧引起的右心室压力、右心室质量、肺动脉重塑和肌肉化的增加大大减弱。此外，与 NTG 对照组相比，低氧暴露对 DnTGF beta RII 小鼠的肺动脉和肺泡胶原含量、肺泡实质中 α-平滑肌肌动蛋白阳性细胞的出现以及全肺细胞外基质分子（包括胶原蛋白 I 和 III、骨膜素和骨桥蛋白）mRNA 的表达的刺激作用被消除。缺氧暴露对两种菌株的全身动脉压或心率均没有影响。这些数据支持以下假设：内源性TGF-β在肺血管适应慢性缺氧中发挥重要作用，TGF-β信号传导的破坏可减轻缺氧引起的肺动脉高压、右心室肥大、肺动脉肥大和肌化、肺泡重塑以及全肺细胞外基质mRNA的表达。
The present study utilized a novel transgenic mouse model that expresses an inducible dominant negative mutation of the transforming growth factor (TGF)-beta type II receptor (DnTGF beta RII mouse) to test the hypothesis that TGF-beta signaling plays an important role in the pathogenesis of chronic hypoxia-induced increases in pulmonary arterial pressure and vascular and alveolar remodeling. Nine- to 10-wk-old male DnTGF beta RII and control nontransgenic (NTG) mice were exposed to normobaric hypoxia (10% O-2) or air for 6 wk. Expression of DnTGF beta RII was induced by drinking 25 mM ZnSO4 water beginning 1 wk before hypoxic exposure. Hypoxia-induced increases in right ventricular pressure, right ventricular mass, pulmonary arterial remodeling, and muscularization were greatly attenuated in DnTGF beta RII mice compared with NTG controls. Furthermore, the stimulatory effects of hypoxic exposure on pulmonary arterial and alveolar collagen content, appearance of alpha-smooth muscle actin-positive cells in alveolar parenchyma, and expression of extracellular matrix molecule ( including collagen I and III, periostin, and osteopontin) mRNA in whole lung were abrogated in DnTGF beta RII mice compared with NTG controls. Hypoxic exposure had no effect on systemic arterial pressure or heart rate in either strain. These data support the hypothesis that endogenous TGF-beta plays an important role in pulmonary vascular adaptation to chronic hypoxia and that disruption of TGF-beta signaling attenuates hypoxia-induced pulmonary hypertension, right ventricular hypertrophy, pulmonary arterial hypertrophy and muscularization, alveolar remodeling, and expression of extracellular matrix mRNA in whole lung.