Beth Israel Deaconess Medical Center, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, Center for Vascular Biology Research, 99 Brookline Avenue, RN-233, Boston, MA 02115, USA.
Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):509-17. doi: 10.1161/ATVBAHA.109.200121. Epub 2009 Dec 30.
Loss-of-function mutations in genes coding for transforming growth factor-beta/bone morphogenetic protein receptors and changes in nitric oxide() (NO()) bioavailability are associated with hereditary hemorrhagic telangiectasia and some forms of pulmonary arterial hypertension. How these abnormalities lead to seemingly disparate pulmonary pathologies remains unknown. Endoglin (Eng), a transforming growth factor-beta coreceptor, is mutated in hereditary hemorrhagic telangiectasia and involved in regulating endothelial NO() synthase (eNOS)-derived NO() production and oxidative stress. Because some patients with pulmonary arterial hypertension harbor ENG mutations leading to haplo insufficiency, we investigated the pulmonary vasculature of Eng(+/-) mice and the potential contribution of abnormal eNOS activation to pulmonary arterial hypertension.
Hemodynamic, histological, and biochemical assessments and x-ray micro-CT imaging of adult Eng(+/-) mice indicated signs of pulmonary arterial hypertension including increased right ventricular systolic pressure, degeneration of the distal pulmonary vasculature, and muscularization of small arteries. These findings were absent in 3-week-old Eng(+/-) mice and were attributable to constitutively uncoupled eNOS activity in the pulmonary circulation, as evidenced by reduced eNOS/heat shock protein 90 association and increased eNOS-derived superoxide ((*)O(2)(-)) production in a BH(4)-independent manner. These changes render eNOS unresponsive to regulation by transforming growth factor-beta/bone morphogenetic protein and underlie the signs of pulmonary arterial hypertension that were prevented by Tempol.
Adult Eng(+/-) mice acquire signs of pulmonary arterial hypertension that are attributable to uncoupled eNOS activity and increased (*)O(2)(-) production, which can be prevented by antioxidant treatment. Eng links transforming growth factor/bone morphogenetic protein receptors to the eNOS activation complex, and its reduction in the pulmonary vasculature leads to increased oxidative stress and pulmonary arterial hypertension.
转化生长因子-β/骨形态发生蛋白受体编码基因突变和一氧化氮（NO（））生物利用度的变化与遗传性出血性毛细血管扩张症和某些形式的肺动脉高压有关。这些异常如何导致看似不同的肺病理学仍然未知。内皮糖蛋白（Eng）是转化生长因子-β的核心受体，在遗传性出血性毛细血管扩张症中发生突变，并参与调节内皮型一氧化氮合酶（eNOS）衍生的 NO（）产生和氧化应激。由于一些肺动脉高压患者携带导致单倍体不足的 ENG 突变，我们研究了 Eng（ +/-）小鼠的肺血管和异常 eNOS 激活对肺动脉高压的潜在贡献。
成年 Eng（ +/-）小鼠的血流动力学、组织学和生化评估以及 X 射线微 CT 成像表明存在肺动脉高压的迹象，包括右心室收缩压升高、远端肺血管退化和小动脉肌化。这些发现不存在于 3 周龄的 Eng（ +/-）小鼠中，并且归因于肺循环中 eNOS 的组成型解偶联活性，这表现为 eNOS/热休克蛋白 90 结合减少和以 BH4 独立方式增加 eNOS 衍生的超氧化物 ((*)O2(-)) 产生。这些变化使 eNOS 对转化生长因子-β/骨形态发生蛋白的调节无反应，并构成肺动脉高压的迹象，这些迹象可被 Tempol 预防。
成年 Eng（ +/-）小鼠出现肺动脉高压的迹象归因于 eNOS 活性解偶联和 (*)O2(-)产生增加，抗氧化治疗可预防这些变化。Eng 将转化生长因子/骨形态发生蛋白受体与 eNOS 激活复合物连接起来，其在肺血管中的减少导致氧化应激增加和肺动脉高压。
