Endothelin‐2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer

Abstract

Endothelin-2 [ET-2; also known as vasoactive intestinal contractor (VIC), in rodents] differs from endothelin-1 (ET-1) by only two amino acids, and unlike the third isoform, endothelin-3 (ET-3), it has the same affinity as ET-1 for both ETA and ETB receptors. It is often assumed that ET-2 would mimic the actions of the more abundant ET-1 and current pharmacological interventions used to inhibit the ET system would also block the actions of ET-2. These assumptions have focused research on ET-1 with ET-2 studied in much less detail. Recent research suggests that our understanding of the ET family requires re-evaluation. Although ET-2 is very similar in structure as well as pharmacology to ET-1, and may co-exist in the same tissue compartments, there is converging evidence for an important and distinct ET-2 pathway. Specifically is has been demonstrated that ET-2 has a key role in ovarian physiology, with ET-2-mediated contraction proposed as a final signal facilitating ovulation. Furthermore, ET-2 may also have a pathophysiological role in heart failure, immunology and cancer. Comparison of ET-2 versus ET-1 mRNA expression suggests this may be accomplished at the level of gene expression but differences may also exist in peptide synthesis by enzymes such as endothelin converting enzymes (ECEs) and chymase, which may allow the two pathways to be distinguished pharmacologically and become separate drug targets. LINKED ARTICLESThis article is part of a themed section on Endothelin. To view the other articles in this section visit http://dx.doi. org/ 10.1111/bph.2013.168.issue-2 Abbreviations ECE-1, endothelin converting enzyme 1; ECE-2, endothelin converting enzyme 2; ELISA, enzyme-linked immunosorbent assay; HIFs, hypoxia-inducible factors; MEK1/2, mitogen-activated protein kinase kinase; MMP-2, matrix metallopeptidase 2; MMP-9, matrix metallopeptidase 9; NEP, neutral endopeptidase; PRKO, progesterone receptor knockout; PMA, phorbol 12-myristate 13 acetate; VIC, vasoactive intestinal contractor IntroductionThe existence of a peptidic endothelium-derived constricting factor was originally proposed in 1985 by Hickey et al. (Hickey et al., 1985) but was identified and named endothelin (ET) by colleagues in 1988 (Yanagisawa et al., 1988). The peptide was renamed ET-1 to reflect the subsequent discovery a year later of human genes encoding two further members of the family, ET-2 and ET-3 (Inoue et al., 1989). The ET peptides act by activating two G-protein couples receptors, ETA and ETB. (Davenport, 2002;Alexander et al., 2011) ET-3 is the only endogenous isoform that distinguishes between the two receptors, having the same affinity at ETB as ET-1 and ET-2 but, at physiological concentrations, has much lower or little affinity for ETA. The established dogma is that ET-2 has the same affinity for both ETA and ETB receptors as ET-1. It is often assumed that ET-2 would mimic the actions of the more abundant peptide, and current pharmacological interventions used to inhibit the ET system would also block the actions o...

Endothelin-2 deficiency causes growth retardation, hypothermia, and emphysema in mice

“…In contrast to the intestine-restricted expression in rodents, human ET-2 expression has been detected in a range of tissues such as heart, lung, kidney, vasculature, ovary, and colon (46). Currently, ET receptor antagonists such as bosentan and ambrisentan are clinically used for the treatment of pulmonary arterial hypertension.…”

Aspects of the endothelin system in colorectal cancer

“…This may be due to failure of precursors of the enteric nervous system and neural crest-derived epidermal melanoblasts to colonize the intestines and skin. At the same time, EDN-3 knockout mice have an identical phenotype (14).…”

“…The EDN-2 gene is present on chromosome 1, while the EDN-3 gene is located on chromosome 20 (12). In comparison to EDN-1, which is distributed in all rat organs examined (13), EDN-2 expression is more restricted to certain human and rat organs, including the intestines (14). Interestingly, EDN-2 has an unequal distribution in the colon; it is immunolocalized at the middle and upper parts of a crypt in the proximal colon and in the base of crypts in the distal colon (15).…”

Implication of Endothelin-2 and Oxidative Stress Biomarkers in Essential Hypertension

“…Endothelin-2 is a member of the endothelin protein family (ET-1, ET-2 and ET-3) of secretory vasoconstrictive peptides that bind to G-protein-coupled receptors (GPCR), ET-RA and ET-RB. ET-1 is known as one of the most powerful vasoconstrictors in the vasculature [7][8][9]. Although, ET-2 is very similar in structure as well as pharmacology to ET-1, studies in knockout mice and in cardiovascular system suggest that ET-2 may have a pathophysiologically distinct role than ET-1, that may be accomplished at the level of gene expression or in their synthesis and therefore, may act as different drug targets.…”