The Causal Relationship between Endothelin-1 and Hypertension: Focusing on Endothelial Dysfunction, Arterial Stiffness, Vascular Remodeling, and Blood Pressure Regulation

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  Figure 1. Schematic representation of the biosynthesis and vascular effects of ET-1 in endothelial and smooth muscle cells. ET-1 is generated by ECs in response to different stimuli. ET-1 mediates vasoconstriction by activating ETA and ETB2 receptors on VSMCs. Vasodilation by ET-1 is mediated through the activation of ETB1 on ECs, which increases the production of NO and PGI2. In addition, ET-1 is a potent mitogen that simulates the growth, proliferation, and migration of VSMCs. Abbreviations: ET-1, endothelin-1; AT II, angiotensin II; Adr, adrenaline; ROS, reactive oxygen species; ADH, antidiuretic hormone; oxLDL, oxidized low-density lipoproteins; ECE, endothelin-converting enzyme; ETA, endothelin receptor subtype A; ETB1, endothelin receptor subtype B1; ETB2 endothelin receptor subtype B2; PLC, phospholipase C; IP3, inositol trisphosphate; DAG, diacylglycerol; Ca2+, calcium ions; COX, cyclooxygenase; AA, arachidonic acid; PGI2, prostacyclin; eNOS, endothelial nitric oxide synthase; L-Arg, L-arginine; NO, nitric oxide; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; sGC, soluble guanylate cyclase; cGMP, cyclic guanosine monophosphate; MAPK, mitogen-activated protein kinase;…

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  Figure 2. Schematic representation of the relationship of ET-1 with oxidative stress in the vascular wall, low-grade inflammation and ED. Increased production of ET-1 may decrease endothelial NO production by suppressing eNOS expression. In addition, ET-1 can mediate the formation of superoxide (O2−) by activating NAD(P)H oxidase, which may reduce the biological activity of NO in the vascular wall due to the formation of peroxynitrite (ONOO−). In ED, the increased production of ET-1 shifted the balance of effects toward increased vasoconstriction, oxidative stress, and inflammation. Abbreviations: ET-1, endothelin-1; ECE, endothelin-converting enzyme; ROS, reactive oxygen species; ETA, endothelin receptor subtype A; ETB1, endothelin receptor subtype B1; ETB2 endothelin receptor subtype B2; PLC, phospholipase C; IP3, inositol trisphosphate; DAG, diacylglycerol; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; PKC, protein kinase C; NAD(P)H Ox, nicotinamide adenine dinucleotide phosphate oxidase; ROS, reactive oxygen species; O2−, superoxide anion; ONOO−, peroxynitrite; NF-κB, nuclear factor kappa B; IL-1, interleukin-1; IL-6, interleukin-6; IL-8, interleukin-8; TNF-α, tumor…

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  Figure 3. Schematic representation of the relationship of ET-1 with arterial stiffness and arterial remodeling as factors for the occurrence of HTN. Increased ET-1 activity may contribute to arterial stiffness in arteriosclerosis and atherosclerosis. These pathological processes significantly reduce the elastic properties of the central conduit arteries, which leads to the manifestation of isolated systolic HTN. Increased systolic and central pulse pressure may lead to eutrophic or hypertrophic remodeling of the small arteries. In particular, hypertrophic remodeling of resistance arteries is a signature of involvement of ET-1 in the hypertensive process. Abbreviations: ET-1, endothelin-1; NO, nitric oxide; PGI2, prostacyclin; NAD(P)H Ox, nicotinamide adenine dinucleotide phosphate oxidase; O2−, superoxide anion; ONOO−, peroxynitrite; NF-κB, nuclear factor kappa B; IL-1, interleukin-1; IL-6, interleukin-6; TNF-α, tumor necrosis factor alpha; MAPK, mitogen-activated protein kinase; TxA2, thromboxane A2; ↑, increased, enhanced activity; ↓, decreased.

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  Figure 4. Schematic representation of synergistic interactions between ET-1 and AT II in the pathogenesis of HTN. ET-1 increases the formation of AT II by enhancing ACE activity. In turn, AT II increases the synthesis of ET-1 by enhancing ECE activity. ET-1 inhibits renin release, but can directly stimulate ALD production. Abbreviations: ET-1, endothelin-1; ppET-1, prepro-ET-1; ECE, endothelin-converting enzyme; AGT, angiotensinogen; AT I, angiotensin I; AT II, angiotensin II; ACE, angiotensin-converting enzyme; ALD, aldosterone.

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  Figure 5. Schematic representation of integrated regulatory effects of ET-1 in HTN. Excessive activation of ET-1 leads to an increase in BP by enhancing the effects of ET-1/ETA signaling in the vasculature, adrenal gland, kidney, nervous system, and heart, which predominate over the BP-lowering effects of ET-1/ETB signaling. The cumulative effect is increased vasoconstriction, increased Na+ and H2O reabsorption, increased sympathetic activity, and a positive inotropic effect on the myocardium, which may lead to the development of HTN. Abbreviations: ET-1, endothelin-1; ETA, endothelin receptor subtype A; ETB, endothelin receptor subtype B; ETB2, endothelin receptor subtype B2; AT I, angiotensin I; AT II, angiotensin II; ACE, angiotensin-converting enzyme; AT1, angiotensin II receptor type 1; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; VP, vasopressin; V1A, vasopressin 1A receptor; V2, vasopressin 2 receptor; CA, catecholamines; α1, alpha-1 adrenergic receptor; ALD, aldosterone; MR, mineralocorticoid receptor; CVC, cardiovascular center; H2O, water; Na+, sodium; +/−, activation/inhibition; ↑, increased.