New Insights Into the Mechanism of Action of Endothelin-1 on Cerebral Microcirculation

Abstract

EVALUATION OF: Faraco G, Moraga A, Moore J, Anrather J, Pickel VM, Iadecola C. Circulating endothelin-1 alters critical mechanisms regulating cerebral microcirculation. Hypertension 62(4), 759–766 (2013). This article reviews a study by Faraco and colleagues that attempts to elucidate the mechanism of modulation of the cerebral blood flow by endothelin (ET) 1. ET1 is one of the most powerful vasoconstrictors and plays an important role in cerebrovascular disease and traumatic brain injury. However, the details of the mechanism of action of ET1 are still unknown. The study used a mouse model with a skull window through which the cortical cerebral blood flow was measured with a laser Doppler probe while various agents were applied. The role of reactive oxygen species and integrity of the blood–brain barrier were also assessed. In addition, the location of the ET receptor was determined by incubation of cortex samples with specific antibodies. ET1 increased mean arterial pressure and attenuated the cerebral blood flow increase stimulated by neuronal activity or the endothelium-dependent acethylcholine but not by A23187. ET1 suppresses the endothelial production of nitric oxide by modulating the endothelial nitric oxide synthase phosphorylation through Rho-associated protein kinase. This effect was mediated by an ETA receptor coupled to phospholipase C via GTP-binding protein and was not related to oxidative stress. The ETA receptor was found in the smooth muscle cells of the pial arterioles and cerebral endothelial cells. The resultant vascular dysfunction may increase the risk of brain ischemia by attenuating the cerebrovascular reserve. Improved understanding of the mechanism of action of ET1 on cerebral microcirculation is likely to stimulate the development of new and promising pharmacological targets.