Dysregulation of Endothelin-1: Implications for Health Disparities in Alzheimer’s Disease

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  Figure 1. The endothelin system and its potential role in Alzheimer’s disease (AD). The synthesis of Endothelin-1 (ET-1), ET-2, and ET-3 occurs from separate mRNAs encoded by EDN-1, EDN-2, and END-3. These preproendothelin mRNAs 1–3 are translated to form preproendothelins 1–3. The three proteins are cleaved via furin-like protease to form Big ETs (Big ET-1, Big ET-2, and Big ET-3). Big-ETs are converted to the active peptide forms of ET-1 via ECE-1 and ECE-2, as well as by metalloproteinases and chymases, ET-2 via ECE-1, ECE-2 and chymase, and ET-3 via ECE-1 and ECE-2, respectively. The active forms bind to cognate G-protein receptors ETA and ETB to activate cellular functions via ETB receptor binding by ET-1–3, resulting in vasodilation and inhibition of growth and inflammation; ET-1 and ET-2 may activate cellular function by binding to ETA receptors on vascular smooth muscle cells (VSMC) and pericytes in the brain and induce vasoconstriction, and cell proliferative responses. High sustained levels of ET-1 among AA and possibly Hispanic/Latino (H/L) populations at high risk for AD could predispose them to conditions of low cerebral blood flow (CBF), leading to neurodegeneration that…

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  Figure 2. Pathophysiology in dysregulation of the ET-1 system with implications for AD. A theoretical model of the effects of ET-1 and Aβ proteins on VSMC and pericyte functions, respectively, in capillaries and components of the neurovascular unit. The effects of ET-1 on VSMC and pericytes include vasoconstriction, the disruption of angiogenesis leading to low CBF. The effects of Aβ proteins on pericytes include pericyte loss and toxicity, induction of ROS, and capillary constriction, all contributing to neuronal toxicity and neurodegeneration that may contribute to AD and ADRD. Note: Figure 2, was revised from a previous report by Alcendor [53]. For the original figure, I acknowledge Pearson Education, Inc. (2014).