Department of Medicine, Vanderbilt Univ. Medical Center, Division of Nephrology, Nashville, TN 37232, USA.
Am J Physiol Regul Integr Comp Physiol. 2010 Mar;298(3):R833-42. doi: 10.1152/ajpregu.00534.2009. Epub 2009 Dec 30.
The bone morphogenetic protein (BMP) type 2 receptor ligand, Bmp2, is upregulated in the peripheral pulmonary vasculature during hypoxia-induced pulmonary hypertension (PH). This contrasts with the expression of Bmp4, which is expressed in respiratory epithelia throughout the lung. Unlike heterozygous null Bmp4 mice (Bmp4(LacZ/+)), which are protected from the development of hypoxic PH, mice that are heterozygous null for Bmp2 (Bmp2(+/-)) develop more severe hypoxic PH than their wild-type littermates. This is associated with reduced endothelial nitric oxide synthase (eNOS) expression and activity in the pulmonary vasculature of hypoxic Bmp2(+/-) but not Bmp4(LacZ/+) mutant mice. Furthermore, exogenous BMP2 upregulates eNOS expression and activity in intrapulmonary artery and pulmonary endothelial cell preparations, indicating that eNOS is a target of Bmp2 signaling in the pulmonary vasculature. Together, these data demonstrate that Bmp2 and Bmp4 exert opposing roles in hypoxic PH and suggest that the protective effects of Bmp2 are mediated by increasing eNOS expression and activity in the hypoxic pulmonary vasculature.
骨形态发生蛋白（BMP）2 型受体配体 Bmp2 在缺氧诱导的肺动脉高压（PH）期间在外周肺血管中上调。这与 Bmp4 的表达形成对比，Bmp4 在整个肺部的呼吸上皮中表达。与杂合子缺失 Bmp4 小鼠（Bmp4(LacZ/+)）免受缺氧性 PH 发展的保护不同，杂合子缺失 Bmp2 的小鼠（Bmp2(+/-)）比其野生型同窝仔鼠发展出更严重的缺氧性 PH。这与缺氧性 Bmp2(+/-)但不是 Bmp4(LacZ/+)突变小鼠肺血管内皮型一氧化氮合酶（eNOS）表达和活性降低有关。此外，外源性 BMP2 上调肺内动脉和肺内皮细胞制剂中的 eNOS 表达和活性，表明 eNOS 是肺血管中 Bmp2 信号的靶标。总之，这些数据表明 Bmp2 和 Bmp4 在缺氧性 PH 中发挥相反的作用，并表明 Bmp2 的保护作用是通过增加缺氧性肺血管中的 eNOS 表达和活性来介导的。
