Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women’s Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA.
Curr Mol Pharmacol. 2011 Nov;4(3):176-86. doi: 10.2174/1874467211104030176.
Endothelin (ET) is one of the most investigated molecules in vascular biology. Since its discovery two decades ago, several ET isoforms, receptors, signaling pathways, agonists and antagonists have been identified. ET functions as a potent endothelium-derived vasoconstrictor, but could also play a role in vascular relaxation. In endothelial cells, preproET and big ET are cleaved by ET converting enzymes into ET-1, -2, -3 and -4. These ET isoforms bind with different affinities to ET(A) and ET(B) receptors in vascular smooth muscle (VSM), and in turn increase Ca(2+), protein kinase C and mitogen-activated protein kinase and other signaling pathways of VSM contraction and cell proliferation. ET also binds to endothelial ET(B) receptors and stimulates the release of nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. ET, via endothelial ET(B) receptor, could also promote ET re-uptake and clearance. While the effects of ET on vascular reactivity and growth have been thoroughly examined, its role in the regulation of blood pressure and the pathogenesis of hypertension is not clearly established. Elevated plasma and vascular tissue levels of ET have been identified in salt-sensitive hypertension and in moderate to severe hypertension, and ET receptor antagonists have been shown to reduce blood pressure to variable extents in these forms of hypertension. The development of new pharmacological and genetic tools could lead to more effective and specific modulators of the vascular ET system for treatment of hypertension and related cardiovascular disease.
内皮素 (ET) 是血管生物学中研究最多的分子之一。自二十年前发现以来，已经鉴定出几种 ET 同工型、受体、信号通路、激动剂和拮抗剂。ET 作为一种有效的内皮衍生血管收缩剂发挥作用，但也可能在血管舒张中发挥作用。在内皮细胞中，前蛋白 ET 和大 ET 被 ET 转换酶切割成 ET-1、-2、-3 和 -4。这些 ET 同工型以不同的亲和力与血管平滑肌 (VSM) 中的 ET(A) 和 ET(B) 受体结合，并依次增加 Ca(2+)、蛋白激酶 C 和丝裂原激活蛋白激酶等 VSM 收缩和细胞增殖的信号通路。ET 还与内皮 ET(B) 受体结合并刺激一氧化氮、前列环素和内皮衍生超极化因子的释放。ET 还可以通过内皮 ET(B) 受体促进 ET 的再摄取和清除。虽然已经彻底研究了 ET 对血管反应性和生长的影响，但它在调节血压和高血压发病机制中的作用尚不清楚。在盐敏感型高血压和中重度高血压中已鉴定出 ET 血浆和血管组织水平升高，并且 ET 受体拮抗剂已被证明可在这些形式的高血压中在不同程度上降低血压。新的药理学和遗传学工具的发展可能会导致针对血管 ET 系统的更有效和更具特异性的调节剂，用于治疗高血压和相关心血管疾病。
