The Sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up
The Sugen 5416/hypoxia mouse model of pulmonary hypertension revisited: long-term follow-up
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DOI：
10.1086/678508
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发表时间：
2014-12-01
影响因子：
2.6
通讯作者：
Kourembanas, Stella
中科院分区：
文献类型：
--
作者：
Vitali, Sally H.;Hansmann, Georg;Kourembanas, Stella
已知血管内皮生长因子受体拮抗剂 Sugen 5416 (SU5416) 与慢性缺氧相结合会导致大鼠出现明显的肺动脉高压 (PH) 并伴有血管闭塞性病变，也会导致小鼠的 PH 值升高。我们试图确定在缺氧 3 周期间每周注射 SU5416 是否会导致小鼠血管闭塞性病变的长期发展以及持续或进行性 PH。雄性 C57BL/6J 小鼠在暴露于 10% 氧气的 3 周内每周注射 SU5416 (SuHx) 或载体 (VehHx)。缺氧暴露 3 周后以及含氧量正常恢复 10 周后，进行超声心动图和血流动力学和肺血管形态测量的侵入性测量。缺氧 3 周后，SuHx 比 VehHx 导致更高的右心室 (RV) 收缩压和 RV 肥大。缺氧十周后，与 VehHx 或含氧量正常的对照小鼠相比，SuHx 小鼠的 RV 收缩压下降，但仍保持升高，但 RV 肥大已解决。缺氧3周和常氧随访10周后，三尖瓣环平面收缩期偏移显着减少，表明收缩期右心室功能下降。在 10 周的随访时间点，SuHx 小鼠肺部几乎没有发现血管闭塞性病变。总之，SU5416 与 3 周缺氧相结合会比单独缺氧引起更严重的小鼠 PH 表型。 SuHx 小鼠的 PH 持续超过 10 周的含氧量正常随访，但没有发生明显的血管闭塞性病变，并且 PH 和 RV 功能障碍均未恶化。 SuHx 小鼠模型是其他 PH 模型的有用辅助，但我们仍将继续寻找能够更好地再现人类表型的小鼠模型。
The combination of a vascular endothelial growth factor receptor antagonist, Sugen 5416 (SU5416), and chronic hypoxia is known to cause pronounced pulmonary hypertension (PH) with angioobliterative lesions in rats and leads to exaggerated PH in mice as well. We sought to determine whether weekly SU5416 injections during 3 weeks of hypoxia leads to long-term development of angioobliterative lesions and sustained or progressive PH in mice. Male C57BL/6J mice were injected with SU5416 (SuHx) or vehicle (VehHx) weekly during 3 weeks of exposure to 10% oxygen. Echocardiographic and invasive measures of hemodynamics and pulmonary vascular morphometry were performed after the 3-week hypoxic exposure and after 10 weeks of recovery in normoxia. SuHx led to higher right ventricular (RV) systolic pressure and RV hypertrophy than VehHx after 3 weeks of hypoxia. Ten weeks after hypoxic exposure, RV systolic pressure decreased but remained elevated in SuHx mice compared with VehHx or normoxic control mice, but RV hypertrophy had resolved. After 3 weeks of hypoxia and 10 weeks of follow-up in normoxia, tricuspid annular plane systolic excursion was significantly decreased, indicating decreased systolic RV function. Very few angioobliterative lesions were found at the 10-week follow-up time point in SuHx mouse lungs. In conclusion, SU5416 combined with 3 weeks of hypoxia causes a more profound PH phenotype in mice than hypoxia alone. PH persists over 10 weeks of normoxic follow-up in SuHx mice, but significant angioobliterative lesions do not occur, and neither PH nor RV dysfunction worsens. The SuHx mouse model is a useful adjunct to other PH models, but the search will continue for a mouse model that better recapitulates the human phenotype.