Daneva Zdravka, Chen Yen-Lin, Ta Huy Q, Manchikalapudi Vamsi, Bazaz Abhishek, Laubach Victor E, Sonkusare Swapnil K
Robert M. Berne Cardiovascular Research Center University of Virginia Charlottesville Virginia USA.
Department of Surgery University of Virginia Charlottesville Virginia USA.
Pulm Circ. 2023 Jan 1;13(1):e12186. doi: 10.1002/pul2.12186. eCollection 2023 Jan.
Endothelial cells (ECs) from small pulmonary arteries (PAs) release nitric oxide (NO) and prostacyclin, which lower pulmonary arterial pressure (PAP). In pulmonary hypertension (PH), the levels of endothelium-derived NO and prostacyclin are reduced, contributing to elevated PAP. Small-and intermediate-conductance Ca-activated K channels (IK and SK)-additional crucial endothelial mediators of vasodilation-are also present in small PAs, but their function has not been investigated in PH. We hypothesized that endothelial IK and SK channels can be targeted to lower PAP in PH. Whole-cell patch-clamp experiments showed functional IK and SK channels in ECs, but not smooth muscle cells, from small PAs. Using a SU5416 plus chronic hypoxia (Su + CH) mouse model of PH, we found that currents through EC IK and SK channels were unchanged compared with those from normal mice. Moreover, IK/SK channel-mediated dilation of small PAs was preserved in Su + CH mice. Consistent with previous reports, endothelial NO levels and NO-mediated dilation were reduced in small PAs from Su + CH mice. Notably, acute treatment with IK/SK channel activators decreased PAP in Su + CH mice but not in normal mice. Further, chronic activation of IK/SK channels decreased PA remodeling and right ventricular hypertrophy, which are pathological hallmarks of PH, in Su + CH mice. Collectively, our data provide the first evidence that, unlike endothelial NO release, IK/SK channel activity is not altered in PH. Our results also demonstrate proof of principle that IK/SK channel activation can be used as a strategy for lowering PAP in PH.
小肺动脉（PA）的内皮细胞（EC）释放一氧化氮（NO）和前列环素，可降低肺动脉压（PAP）。在肺动脉高压（PH）中，内皮源性NO和前列环素水平降低，导致PAP升高。小电导和中电导钙激活钾通道（IK和SK）——血管舒张的另外两个关键内皮介质——也存在于小肺动脉中，但它们在PH中的功能尚未得到研究。我们推测，内皮IK和SK通道可作为降低PH患者PAP的靶点。全细胞膜片钳实验表明，小肺动脉的EC中有功能性IK和SK通道，但平滑肌细胞中没有。使用PH的SU5416加慢性缺氧（Su + CH）小鼠模型，我们发现与正常小鼠相比，通过EC IK和SK通道的电流没有变化。此外，IK/SK通道介导的小肺动脉舒张在Su + CH小鼠中得以保留。与之前的报道一致，Su + CH小鼠小肺动脉中的内皮NO水平和NO介导的舒张作用降低。值得注意的是，用IK/SK通道激活剂进行急性治疗可降低Su + CH小鼠的PAP，但对正常小鼠无效。此外，在Su + CH小鼠中，IK/SK通道的慢性激活减少了PA重塑和右心室肥大，这是PH的病理特征。总的来说，我们的数据首次证明，与内皮NO释放不同，IK/SK通道活性在PH中没有改变。我们的结果还证明了IK/SK通道激活可作为降低PH患者PAP的一种策略。
