Endothelin-1: The Yin and Yang on Vascular Function

Abstract

Endothelin-1 (ET-1) is a vasoconstrictor secreted by endothelial cells, which acts as the natural counterpart of the vasodilator nitric oxide (NO). ET-1 contributes to vascular tone and regulates cell proliferation through activation of ETA and ETB receptors. Physical factors such as shear stress, or stimuli including thrombin, epinephrine, angiotensin II, growth factors, cytokines and free radicals enhance secretion of ET-1. By contrast, mediators like nitric oxide (NO), cyclic GMP, atrial natriuretic peptide, and prostacyclin reduce the release of endogenous ET-1. Thus, under normal conditions, the effects of the ET-1 are carefully regulated through inhibition or stimulation of ET-1 release from endothelium. Endothelial dysfunction is one of the earliest landmarks of vascular abnormalities. Altered function of endothelium may result from absolute decrease in bioavailability of NO as well as from relative augment in ET-1 synthesis, release or activity. Imbalance in the production of vasodilator and vasoconstrictor agents may contribute to the onset of hemodynamic disorders. Since dysregulation of the endothelin system is important in the pathogenesis of several cardiovascular diseases, the ETA and ETB receptors are attractive therapeutic targets for disorders associated with elevated ET-1 levels. ET receptor antagonists may be regarded as disease-modifying agents thanks to their ability to preserve endothelial integrity when the endothelin system is overactive. This review summarizes the current knowledge on the role of ET-1 in experimental hypertension and describes recent findings on the involvement of MAPK signalling pathways in ET-1 release in hypertension associated with insulin resistance. Moreover, therapeutic applications of ET-1 receptor blockers are also discussed.

Effect of Endothelin 1 Genotype on Blood Pressure Is Dependent on Physical Activity or Fitness Levels

“…6,7 Only EDN1 is expressed constitutively on vascular endothelium and thereby affects vasomotor tone. 8 DNA sequence variations in the EDN1 gene locus have been reported to be associated with blood pressure levels and hypertension in some populations. 9 -11 An interesting finding of previous studies exploring the relationships among hemodynamic traits and the EDN1 genotype is the seemingly more pronounced association in overweight or obese individuals.…”

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

“…NO bioavailability depends on several multiple factors, ranging from the efficiency of the producing enzyme endothelial NO synthase (eNOS) to the speed of conversion of NO itself to more stable nitrate/nitrite derivatives. The dynamic, highly regulated physiological production of NO in the endothelium may be disrupted when eNOS protein expression is decreased, when eNOS substrates and/or co-factors are insufficient, when enzymatic activity of eNOS is impaired or uncoupled, or when the production of endothelial mediators with opposing vascular effects is relatively increased [9,14]. The deficiency of NO bioavailability and the increased reactive oxygen species (ROS) and proinflammatory factors are requisite hallmarks for endothelial dysfunction [15].…”

Cardiovascular risk factors regulate the expression of vascular endothelin receptors

“…In contrast, the ET B receptors are primarily located on VEC (also named ET B1 ) and mediate vasodilatation and inhibition of VSMC proliferation through the release of nitric oxide (NO) and prostacyclin (PGI 2 ) (Marasciulo et al, 2006;Schneider et al, 2007). A subpopulation of contractile ET B receptors (named ET B2 ) also exists in the VSMC and mediates vasoconstriction (Adner et al, 1996;Gray et al, 2000) and proliferation (Janakidevi et al, 1992) (Fig.…”

“…This results in contraction and proliferation of VSMC through activation of intracellular signaling molecules such as phospholipase C, intracellular Ca 2+ , protein kinase C (PKC) and extracellular signal-regulated kinase 1 and 2 (ERK1/2). The ET B receptor stimulates the Gi and the Gq/11 families of proteins in VSMC and VEC (Gohla et al, 2000;Cramer et al, 2001;Marasciulo et al, 2006). ET-1 binds tightly to the ET A receptor and gives rise to a strong, long-lasting contraction with a low receptor turnover (Sudjarwo et al, 1994).…”