The Children's Hospital, Zhejiang Univ. School of Medicine, Hangzhou, Zhejiang province, P.R. China, 310003.
Am J Physiol Lung Cell Mol Physiol. 2013 Dec;305(11):L856-65. doi: 10.1152/ajplung.00179.2013. Epub 2013 Sep 27.
Chronic hypoxia pulmonary hypertension (CH-PHT) in adulthood is likely to be of fetal origin following intrauterine growth retardation (IUGR). Oxygen (O₂)-sensitive voltage-gated potassium channels (Kv channels) in resistance pulmonary artery smooth muscle cells (PASMCs) play an important role in scaling pulmonary artery (PA) pressure. Expression and functional changes of Kv channels are determined, in part, by embryonic development. We hypothesized that O₂-sensitive Kv channels play an important role in exaggerated CH-PHT following IUGR. We established a rat model of IUGR by restricting maternal food during the entire pregnancy and exposed IUGR rats and their age-matched controls aged 12 wk to hypoxia for 2 wk. We found that hypoxia exposure significantly induced increased PA pressure and thicker smooth muscle layer in the IUGR group relative to controls. We compared the constriction of the resistance PA to inhibitors of K⁺ channels, 4-aminopyridine (4-AP), tetraethylammonium, and BaCl₂. Despite the thickness of the smooth muscle layer, the constriction to 4-AP was significantly reduced in the IUGR group exposed to hypoxia. Consistent with these changes in pulmonary vascular reactivity, 2 wk of hypoxia induced weaker 4-AP-sensitive Kv currents in a single IUGR PASMC. Moreover, after 2 wk of hypoxia, Kv1.5 expression in resistance PAs decreased significantly in the IUGR group. Overexpression of Kv1.5 in cultured PASMCs could offset hypoxia-induced cell proliferation and hypoxia-inhibited Kv currents in the IUGR group. These results suggest that the inhibited expression of Kv1.5 in PASMCs contribute to the development of exaggerated CH-PHT in IUGR rats during adulthood.
成人慢性低氧性肺动脉高压（CH-PHT）很可能是宫内生长迟缓（IUGR）后胎儿起源的。在阻力性肺动脉平滑肌细胞（PASMCs）中，氧（O₂）敏感电压门控钾通道（Kv 通道）在调节肺动脉（PA）压力方面发挥着重要作用。Kv 通道的表达和功能变化部分取决于胚胎发育。我们假设 O₂敏感的 Kv 通道在 IUGR 后过度的 CH-PHT 中发挥重要作用。我们通过在整个怀孕期间限制母体食物来建立 IUGR 大鼠模型，并使 IUGR 大鼠及其 12 周龄的年龄匹配对照在缺氧环境中暴露 2 周。我们发现，与对照组相比，缺氧暴露显著导致 IUGR 组的 PA 压升高和平滑肌层增厚。我们比较了阻力性 PA 对 K⁺通道抑制剂（4-氨基吡啶[4-AP]、四乙铵和 BaCl₂）的收缩情况。尽管平滑肌层较厚，但在缺氧的 IUGR 组中，对 4-AP 的收缩明显减少。与肺血管反应性的这些变化一致，2 周的缺氧导致单个 IUGR PASMC 中 4-AP 敏感的 Kv 电流减弱。此外，在缺氧 2 周后，IUGR 组阻力性 PA 中的 Kv1.5 表达显著下降。在培养的 PASMCs 中过表达 Kv1.5 可以抵消缺氧诱导的 IUGR 组细胞增殖和抑制的 Kv 电流。这些结果表明，PASMCs 中 Kv1.5 的表达抑制导致 IUGR 大鼠在成年期过度发展 CH-PHT。
