Endothelin

Davenport, Anthony P.; Hyndman, Kelly A.; Dhaun, Neeraj; Southan, Christopher; Kohan, Donald E.; Pollock, Jennifer S.; Pollock, David M.; Webb, David J.; Maguire, Janet J.

doi:10.1124/pr.115.011833

Cited by 579 publications

(578 citation statements)

References 629 publications

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“…The ET pathway is activated by three ligands: ET-1, ET-2 and ET-3, of which ET-1 is the most common isoform [10,11]. The ET-1 precursor protein, prepro-ET-1, is cleaved by furin into big-ET-1, which is subsequently processed to its active form by the endothelin-converting enzyme-1 and binds and activates two different G-protein coupled receptors, ETA and ETB, with equal affinity.…”

mentioning

confidence: 99%

“…The ET-1 precursor protein, prepro-ET-1, is cleaved by furin into big-ET-1, which is subsequently processed to its active form by the endothelin-converting enzyme-1 and binds and activates two different G-protein coupled receptors, ETA and ETB, with equal affinity. The ETA receptor is located at the cell surface of vascular smooth muscle cells and induces vasoconstriction and cell proliferation by activating phospholipase C, whereas the ETB receptor is located mainly in the cell membrane of the endothelium and induces vasodilation by regulating the release of NO and PGI 2 [11,12]. Furthermore, ET-1 promotes cell growth, cell adhesion and thrombosis and is increased in lung tissue of patients with pulmonary hypertension (PH).…”

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confidence: 99%

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Pulmonary vascular development in congenital diaphragmatic hernia

et al. 2018

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Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly characterised by a diaphragmatic defect, persistent pulmonary hypertension (PH) and lung hypoplasia. The relative contribution of these three elements can vary considerably in individual patients. Most affected children suffer primarily from the associated PH, for which the therapeutic modalities are limited and frequently not evidence based. The vascular defects associated with PH, which is characterised by increased muscularisation of arterioles and capillaries, start to develop early in gestation. Pulmonary vascular development is integrated with the development of the airway epithelium. Although our knowledge is still incomplete, the processes involved in the growth and expansion of the vasculature are beginning to be unravelled. It is clear that early disturbances of this process lead to major pulmonary growth abnormalities, resulting in serious clinical challenges and in many cases death in the newborn. Here we provide an overview of the current molecular pathways involved in pulmonary vascular development. Moreover, we describe the abnormalities associated with CDH and the potential therapeutic approaches for this severe abnormality. Normal pulmonary vascular developmentHuman lung development can be divided into different stages based on histology, starting with the embryonic stage at 4 weeks of gestation, followed by the pseudoglandular stage in which branching of the lung buds continues. During the canalicular stage, starting at ∼16 weeks of gestation, the terminal bronchioli are formed. From 24 weeks of gestation until term, the saccular stage, airspaces widen and alveoli are formed. During the alveolar stage, which persists into the postnatal period up to 3 years of age, maturation of the airways occurs [1]. Concomitant with the expansion of the airways is the adaptation of the microvasculature to optimise the exchange of oxygen and carbon dioxide between the blood and the airways. We and others have shown that very early in lung development pulmonary vessels are present and connected to the systemic circulation. The vasculature develops in close relation with the airways and is a rate-limiting factor in branching morphogenesis [2][3][4]. This implies that the pulmonary vasculature plays an important role in lung development. The formation of new blood vessels primarily occurs through

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confidence: 99%

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confidence: 99%

Pulmonary vascular development in congenital diaphragmatic hernia

et al. 2018

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“…ET B receptors on the pulmonary endothelium represent the primary site of plasma ET‐1 clearance 10, 40. Thus, we evaluated pulmonary ET receptor binding in VEETKO and flox mice.…”

Section: Resultsmentioning

confidence: 99%

“…ET‐1 is a nanomolar potent peptide produced by diverse cell types throughout the body that functions in autocrine and paracrine signaling 9, 10. Multiple studies have demonstrated an increase in plasma ET‐1 levels in response to laboratory‐induced acute psychosocial stress in healthy, at risk, and diseased human subjects 2, 11, 12, 13, 14, 15, 16.…”

Section: Introductionmentioning

confidence: 99%

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

Fox

Becker

Loria

et al. 2018

JAHA

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BackgroundAcute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor.Methods and ResultsAdult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in both genotypes; however, this response was significantly blunted in vascular endothelium‐specific ET‐1 knockout mice compared with control mice that were homozygous for the floxed allele. In mice pretreated for 3 days with the endothelin A antagonist, ABT‐627, or the dual endothelin A/B receptor antagonist, A‐182086, the pressor response to CSS was similar between genotypes. CSS significantly increased plasma ET‐1 levels in control mice that were homozygous for the floxed allele. CSS failed to elicit an increase in plasma ET‐1 in vascular endothelium‐specific ET‐1 knockout mice. Telemetry frequency domain analyses suggested similar autonomic responses to stress between genotypes, and isolated resistance arteries demonstrated similar sensitivity to α1‐adrenergic receptor‐mediated vasoconstriction.ConclusionsThese findings specify that acute stress‐induced activation of endothelium‐derived ET‐1 and subsequent endothelin A receptor activation is a novel mediator of the blood pressure response to acute psychosocial stress.

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“…The situation in essential hypertension is, however, less clear. 29 In SHR, the role of the renin-angiotensin system is well established. 30 A potential role of the endothelin system in the arterial functional and structural changes is, however, less clear.…”

Section: Discussionmentioning

confidence: 99%

Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR

et al. 2017

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Endothelin 1 (ET-1), a potent vasoconstrictor, pro-mitogenic and pro-inflammatory peptide, may promote development of endothelial dysfunction and arterial remodeling. ET-1 can be formed through cleavage of big-ET-1 by endothelin-converting enzyme (ECE) or neutral endopeptidase (NEP). We investigated whether chronic treatment with the novel dual NEP/ECE inhibitor SOL1 improves functional and structural properties of resistance-sized arteries of 32-week-old male spontaneously hypertensive rats (SHR). SHR received a chronic 4-week treatment with SOL1, losartan or hydralazine. We then compared effects of inhibition of NO synthase (NOS) (100 μM L-NAME), blockade of ET A -and ET B -receptors (10 μM bosentan) and stimulation of the endothelium with 0.001-10 μM acetylcholine (ACh) in isolated third-order mesenteric resistance arteries. Losartan and hydralazine significantly lowered blood pressure. Losartan decreased the media-to-lumen ratio of resistance arteries. L-NAME (1) increased arterial contractile responses to K + (5.9-40 mM) in the losartan, SOL1 and vehicle group and (2) increased the sensitivity to phenylephrine (PHE; 0.16-20 μM) in the SOL1 group but not in the losartan, hydralazine and vehicle group. Relaxing responses to ACh in the absence or presence of L-NAME during contractions induced by either 10 μM PHE or 40 mM K + were not altered by any in vivo treatment. Acute treatment with bosentan did, however, significantly improve maximal relaxing responses involving endothelium-derived nitric oxide and -hyperpolarizing factors in the SOL1 group but not in the losartan, hydralazine or vehicle group. Thus, chronic inhibition of NEP/ECE improved basal endothelial function but did not alter blood pressure, resistance artery structure and stimulated endothelium-dependent relaxing responses in 32-week-old SHR.

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Endothelin

Cited by 579 publications

References 629 publications

Pulmonary vascular development in congenital diaphragmatic hernia

Pulmonary vascular development in congenital diaphragmatic hernia

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

Dual NEP/ECE inhibition improves endothelial function in mesenteric resistance arteries of 32-week-old SHR

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