Division of Cardiothoracic Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
Division of Cardiothoracic Surgery, Rhode Island Hospital, Alpert Medical School of Brown University, Providence, RI, USA.
Eur J Cell Biol. 2022 Apr;101(2):151208. doi: 10.1016/j.ejcb.2022.151208. Epub 2022 Feb 8.
The vascular endothelium is an important regulator of vascular reactivity and preserves the balance between vasoconstrictor and vasodilator tone during normal physiologic conditions. Example endothelial-derived vasoconstrictors include endothelin-1 and thromboxane A2; example vasodilators include nitric oxide and prostacyclin. A growing body of evidence points to the existence of a non-nitric oxide, non-prostacyclin endothelium-derived vasodilatory factor of currently unclear identity, often referred to as endothelium-derived hyperpolarizing factor (EDHF). Recent research testifies to the significance of EDHF in endothelium-dependent vascular smooth muscle relaxation. Special emphasis has been placed on the role of small conductance calcium-activated potassium channels (SK) in facilitating the endothelial and vascular responses to EDHF across the microcirculation, including coronary, mesenteric, and pulmonary vascular beds. Meanwhile, decreased activity of endothelial SK channel activity has been implicated in the pathology of a variety of disease states that alter the balance between vasodilator and vasoconstrictor tone. Hence the primary goal of this review is to characterize the physiology of endothelial SK channels in the microvasculature under normal and pathological conditions. Themes of regulation and dysregulation of SK channel activity through the action of protein kinases, reactive oxygen species, and byproducts of intermediary metabolism provide unifying principles to tie together vascular pathology in altered metabolic states ranging from hypertension to diabetes, to ischemia-reperfusion. A comprehensive understanding of SK channel pathophysiology may provide a foundation for development of new therapeutics targeting SK channels, particularly SK channel potentiators, that may have widespread application for many chronic disease states.
血管内皮细胞是血管反应性的重要调节者，在正常生理条件下维持血管收缩剂和血管扩张剂之间的平衡。内皮细胞衍生的血管收缩剂包括内皮素-1 和血栓素 A2；血管扩张剂包括一氧化氮和前列环素。越来越多的证据表明，存在一种非一氧化氮、非前列环素的内皮衍生血管舒张因子，其目前身份不明，通常称为内皮衍生超极化因子（EDHF）。最近的研究证明了 EDHF 在内皮依赖性血管平滑肌松弛中的重要性。特别强调了小电导钙激活钾通道（SK）在促进内皮细胞和血管对 EDHF 的反应中的作用，包括冠状动脉、肠系膜和肺血管床。同时，内皮 SK 通道活性的降低被认为与多种改变血管舒张剂和血管收缩剂平衡的疾病状态的病理学有关。因此，本综述的主要目标是描述正常和病理条件下微血管内皮 SK 通道的生理学。通过蛋白激酶、活性氧和中间代谢产物的作用调节和失调 SK 通道活性的主题为改变代谢状态的血管病理学提供了统一的原则，从高血压到糖尿病，再到缺血再灌注。对 SK 通道病理生理学的全面理解可能为开发针对 SK 通道的新型治疗方法提供基础，特别是 SK 通道增强剂，这些方法可能广泛应用于许多慢性疾病状态。
