Down But Not Out
An Emerging Role for the B-Type Endothelin Receptor in Placental Ischemia–Induced Hypertension
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See related article, pp 632–643
Since its discovery in 1987, the vasoactive peptide endothelin has been implicated in the physiology of a broad range of organ systems and tissues, and its role in the pathophysiology of disease is widely investigated.1 The endothelin system is complex and unique, with many of its functions remaining unclear despite intensive research. The active ligand, endothelin-1 (ET-1), is derived from a pre-pro endothelin peptide, which is cleaved to big ET-1 and then to active ET-1. Secretion seems to be directional from the basolateral side of endothelial cells where it is secreted to act in an autocrine or paracrine manner on 1 of 2 different G-protein–coupled receptors with opposing effects on vascular tone.1 Endothelin receptor type A (ETAR) mediates vasoconstriction on vascular smooth muscle cells, whereas endothelin receptor type B (ETBR) generates either endothelial-dependent vasorelaxation or sequestration and clearance of ET-1 from circulation.1 Alternatively, by signaling through ETBR on endothelial cells, ET-1 is recognized as a proangiogenic autocrine factor that works in concert with vascular endothelial growth factor to promote angiogenesis.2
ET-1 is recognized as one of the most potent vasoconstrictors and has been implicated in several forms of hypertension. However, because increases in circulating concentrations of the peptide are often not evident, the exact role of endothelin has remained enigmatic in hypertensive disorders such as preeclampsia. Although circulating ET-1 is not frequently observed to be increased in preeclampsia and relevant animal models of the syndrome, …