Kidney diseases are among the most prevalent conditions worldwide, impacting over 850 million individuals. They are categorized into acute kidney injury and chronic kidney disease. Current preclinical and clinical trials have demonstrated that endothelin (ET) is linked to the onset and progression of kidney disease. In kidney diseases, pathological conditions such as hyperglycemia, acidosis, insulin resistance, and elevated angiotensin II levels lead to an increase in ET. This elevation activates endothelin receptor type A, resulting in harmful effects like proteinuria and a reduced glomerular filtration rate (GFR). Therefore, to slow the progression of kidney disease, endothelin receptor antagonists (ERAs) have been proposed as promising new therapies. Numerous studies have demonstrated the efficacy of ERAs in significantly reducing proteinuria and improving GFR, thereby slowing the progression of kidney diseases. This review discusses the mechanisms of action of ERAs in treating kidney disease, their efficacy and safety in preclinical and clinical studies, and explores future prospects for ERAs.

Dysfunction of ocular blood flow (BF) is believed to be one of the causes of glaucomatous pathology. However, whether this dysfunction is indeed a cause or is actually a consequence of optic nerve degeneration remains controversial. Here, we established a new animal model of chronic BF reduction in the retina to mimic glaucoma. We found that retinal BF in rats, as measured with laser speckle flowgraphy, was significantly reduced 3 wk after an intravitreal injection of AAV2-human endothelin-1 (AAV2-hEDN1). The number of retinal ganglion cells was also reduced in rats that received AAV2-hEDN1 injection. Immunostaining signals for GFAP and the endothelin-B receptor were enhanced in the rat retinas after AAV2-hEDN1 injection. Moreover, mRNA levels of Ripk1/Ripk3 and Tnf in the retina increased, and glutathione levels in the aqueous humor decreased in rats that received AAV2-hEDN1 injection. Our findings demonstrate that endothelin-induced chronic retinal BF reduction leads to increased astrocyte activation and oxidative stress, which in turn induces retinal ganglion cell necroptosis. This suggests that methods to improve ocular BF have potential as novel therapies for glaucoma.

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells that form the interface between the hepatic vasculature and parenchymal cells, playing a crucial role in maintaining hepatic homeostasis. Under pathological conditions, LSECs undergo capillarization, marked by the loss of fenestrae and formation of a basement membrane, thereby impairing microcirculation and promoting fibrosis. Beyond capillarization, LSECs experience a spectrum of pathological changes-including angiogenesis, endothelial-to-mesenchymal transition (EndMT), autophagy, and senescence-all of which contribute to fibrogenesis through distinct molecular pathways. Moreover, LSECs orchestrate liver fibrotic remodeling through dynamic crosstalk with hepatic stellate cells (HSCs), hepatocytes, Kupffer cells, and immune cells, exerting both pro- and anti-fibrotic effects. This review comprehensively summarizes LSECs dysfunction in hepatic fibrosis, with a particular focus on intercellular communication and emerging therapeutic strategies. Elucidating the regulatory networks that govern LSECs behavior may uncover new opportunities for the diagnosis and treatment of chronic liver disease.

The involvement of endothelin-1 (ET-1) in the maintenance of kidney function as well as its role in renal pathophysiology has been appreciated for decades; however, there still exist important gaps in knowledge in our understanding of the mechanistic pathways activated by this system in the kidney. The purpose of this article is to review recent advances in the field, as well as to underscore areas that need more investigation, with an emphasis on the interplay of ET-1 with inflammation, sex differences, circadian rhythms of renal function, the most recent clinical trials involving the ET-1 system, and the interaction between microRNAs and the ET-1 system.

Metabolic syndrome (MetS) is a multifaceted disease associated with heart failure (HF), which affects the vascular system. The endothelin (ET) system is a key player in MetS and HF; therefore, targets for ET receptors are of therapeutic interest.

This study sought to evaluate the effects of macitentan, a dual endothelin receptor antagonist (ERA), in a rat model of MetS-induced heart failure with preserved ejection fraction (HFpEF).

We assessed in 12-week-old Zucker fa/fa rats the effects of macitentan (10 mg/kg/day as a food additive for short-term/7- or long-term/90-day treatment) on right ventricular (RV) and left ventricular (LV) function/remodelling (MRI), RV and LV haemodynamics (catheterization) and RV and LV coronary function (myograph).

After 7- and 90-days, untreated Zucker fa/fa rats presented isolated LV diastolic dysfunction (illustrated by elevated LV end-diastolic pressure [EDP] and LV end-diastolic pressure-volume relationship [EDPVR] without changes in LV EDPVR). This was associated with increased collagen deposition and impaired endothelium-dependent coronary artery relaxation. Macitentan 7- and 90-day treatment significantly decreased blood pressure and prevented LV, RV and coronary dysfunctions and long-term treatment reduced LV collagen density. Moreover, 7- and 90-day macitentan treatment significantly reduced cardiac inflammation and reactive oxygen species (ROS) production.

Dual ERA macitentan improved both LV and RV diastolic dysfunction. This was associated with improved coronary vasodilation, diminished cardiac oxidative stress and improved blood composition. These results suggest that antagonizing the ET system with macitentan is a promising approach to treat HFpEF and its complications.

Cardiomyopathy is an anatomical and pathologic condition that is related to the cardiac muscle or left ventricular failure. A diverse range of illnesses known as cardiomyopathies often result in progressive heart failure with high morbidity and death rates. Primary cardiomyopathies are hereditary, mixed, or adopted. Secondary cardiomyopathies are infiltrative, harmful, or pathogenic. The activation of many paracrine, autocrine, and neuroendocrine factors is closely linked to pathological left ventricular (LV) deformation. After the myocardial injury, in the context of higher LV wall pressure and haemodynamic disturbance, these variables are raised. New therapy techniques have been focused on these novel targets after recent studies revealed that endothelin, nitric oxide or cytokines may be implicated in the remodelling process. Vasoconstrictive peptide endothelin-1 (ET-1) is mostly generated in the endothelium and works by binding to the ETA- and ETB-endothelin receptors (ET-Rs). The expression of both ET-Rs is widespread in cardiac tissues. Heart failure, pulmonary arterial hypertension, hypertension, cardiomyopathy, and coronary artery disease are just a few of the cardiovascular disorders for which the endothelin system has been shown to play a crucial role over the years. The occurrence, pathogenesis, and natural history of endothelin antagonists in cardiomyopathies are currently not well understood, and specific aspects of their treatment responses have not received comprehensive attention. Therefore, in this study, we address the variable degrees of success that have been achieved in treating cardiomyopathy using endothelin-targeting treatments, such as endothelin receptor antagonists.

Bosentan is a dual endothelin receptor antagonist widely used in the treatment of pulmonary artery hypertension. However, there are few reports on the pharmacokinetics (PK) and bioequivalence of bosentan dispersible tablets (32 mg) in the Chinese population. This study aimed to evaluate the PK characteristics and bioequivalence of the test and reference formulations of bosentan dispersible tablets in healthy Chinese volunteers under fasting and fed conditions. A randomized, single-dose, 2-sequence, 2-period crossover study (fasting) and a 4-period replicate crossover study (fed) were conducted with 48 and 30 healthy volunteers, respectively. The bosentan plasma concentrations were measured by a validated ultra-performance liquid chromatography coupled with a tandem mass spectrometry method, and PK parameters were analyzed using noncompartmental methods. The bioequivalence statistical analysis showed that 90% confidence intervals for the geometric mean ratios of peak plasma concentration, area under the concentration-time curve (AUC) from time zero to the last measurable concentration, and AUC from time zero to infinity for the test and reference formulations were within the bioequivalence range of 80%-125% under both fasting and fed conditions. After the administration of bosentan dispersible tablets under fed conditions, the systemic exposure (based on AUC from time zero to infinity) was increased by approximately 15%-20%. These findings confirm the bioequivalence of the 2 formulations, and both formulations were well tolerated, with no safety-related adverse events reported. Given the wide therapeutic dose range of bosentan dispersible tablets for the treatment of pulmonary artery hypertension in children, the impact of food on its PK is not considered clinically significant.

The current method for generating an animal model of spinal cord (SC) infarction is highly invasive and permits only short-term observation, typically limited to 28 days.

We aimed to establish a rat model characterised by long-term survival and enduring SC dysfunction by inducing selective ischaemic SC damage.

In 8-week-old male Wistar rats, a convection-enhanced delivery technique was applied to selectively deliver endothelin-1 (ET-1) to the anterior horn of the SC at the Th13 level, leading to SC infarction. The Basso, Beattie and Bresnahan (BBB) locomotor score was assessed for 56 days. The SC was examined by a laser tissue blood flowmeter, MRI, immunohistochemistry, triphenyl tetrazolium chloride (TTC) staining, Western blots and TUNEL staining.

The puncture method was used to bilaterally inject 0.7 µL ET-1 (2.5 mg/mL) from the lateral SC into the anterior horns (40° angle, 1.5 mm depth) near the posterior root origin. Animals survived until day 56 and the BBB score was stably maintained (5.5±1.0 at day 14 and 6.2±1.0 at day 56). Rats with BBB scores ≤1 on day 1 showed stable scores of 5-6 after day 14 until day 56 while rats with BBB scores >1 on day 1 exhibited only minor dysfunction with BBB scores >12 after day 14. TTC staining, immunostaining and TUNEL staining revealed selective ischaemia and neuronal cell death in the anterior horn. T2-weighted MR images showed increasing signal intensity at the SC infarction site over time. Western blots revealed apoptosis and subsequent inflammation in SC tissue after ET-1 administration.

Selective delivery of ET-1 into the SC allows for more precise localisation of the infarcted area at the targeted site and generates a rat SC infarction model with stable neurological dysfunction lasting 56 days.

The management of acute heart failure (AHF) is becoming increasingly complex, especially in patients with multiple comorbidities. Endothelin-1 (ET-1), a vasoconstrictive peptide, is an important mediator of neurohormonal activation, endothelial dysfunction, and cardiac remodeling-key processes involved in the pathogenesis of AHF. The aim of our study was to evaluate the diagnostic and prognostic performance of ET-1 in multimorbid AHF patients, compared to established markers such as amino terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI). We conducted a single-center prospective study including 76 patients; 54 with AHF and 22 serving as controls. Upon admission, all patients underwent a comprehensive clinical, echocardiographic, and laboratory evaluation, including plasma ET-1 measurement using the enzyme-linked immunosorbent assay (ELISA) method. Receiver operating characteristic (ROC) curve and area under the curve (AUC) analysis were performed to assess the diagnostic and prognostic performance of ET-1 in comparison to NT-proBNP and hs-cTnI. ET-1 levels were considerably higher in AHF patients than in controls (p = 0.02), with an AUC of 0.954, showing comparable diagnostic accuracy with NT-proBNP (AUC = 0.997), alongside strong correlations with signs of systemic congestion, increased hospital stay, and ventricular dysfunction. ET-1 had the strongest predictive accuracy for in-hospital mortality (AUC = 0.781, p = 0.026), outperforming NT-proBNP and hs-cTnI. For 30-day mortality, ET-1 remained a reliable predictor (AUC = 0.784, p = 0.016). However, as the follow-up period extended to one year, its predictive power declined, confirming ET-1's prognostic efficacy only for short-term outcomes. Moreover, ET-1 levels were not influenced by the presence of comorbidities, demonstrating its potential as an independent biomarker. Our findings support that ET-1 is a valuable biomarker for both diagnosis and short-term prognosis in the assessment of multimorbid AHF patients.

Coronary artery ectasia (CAE), defined as a 1.5-fold or greater enlargement of a coronary artery segment compared to the adjacent normal coronary artery, is frequently associated with atherosclerotic coronary artery disease (CAD). Membrane-bound endothelin converting enzyme-1 (ECE-1) is involved in the maturation process of the most potent vasoconstrictor ET-1. Polymorphisms in the endothelin (ET) gene family have been shown associated with the development of atherosclerosis. This study aims to investigate the effects of rs213045 and rs2038089 polymorphisms in the ECE-1 gene which have been previously shown to be associated with atherosclerosis and hypertension (HT), in CAE patients. Ninety-six CAE and 175 patients with normal coronary arteries were included in the study. ECE-1b gene variations rs213045 and rs2038089 were determined by real-time PCR. The frequencies of rs213045 C > A (C338A) CC genotype (60.4% vs. 35.4%, p < 0.001) and rs2038089 T > C T allele (64.58% vs. 35.42%, p = 0.017) were higher in the CAE group compared to the control group. The multivariate regression analysis showed that the ECE-1b rs213045 CC genotype (p = 0.001), rs2038089 T allele (p = 0.017), and hypercholesterolemia (HC) (p = 0.001) are risk factors for CAE. Moreover, in nondiabetic individuals of the CAE and control groups, it was observed that the rs213045 CC genotype (p < 0.001), and rs2038089 T allele (p = 0.003) were a risk factor for CAE, but this relationship was not found in the diabetic subgroups of the study groups (p > 0.05). These results show that ECE-1b polymorphisms may be associated with the risk of CAE and this relationship may change according to the presence of type II diabetes.

Despite successful management of pulmonary complication with fluid restriction protocol in aneurysmal subarachnoid hemorrhage (aSAH) patients treated with clazosentan, management of symptoms related to mucosal edema, such as diarrhea, stuffy nose, and difficulty in breathing, remains challenging. Hence, we investigated the effect of Goreisan shown to be effective in the treatment of symptoms related with mucosal edema in aSAH patients treated with clazosentan. Patients with aSAH who received clazosentan for vasospasm after aneurysm obliteration were prospectively enrolled in the study. Fluid balance parameters and the incidence of vasospasm, pulmonary edema, mucosal edema-related symptom (such as diarrhea and swelling of the nasal mucosa) were compared between these patients treated with Goreisan (Group G) and without Goreisan (Group NG). As results, Groups NG and G comprised 29 and 40 consecutive patients, respectively. No significant differences in fluid intake, urine volume, frequency of furosemide injection, incidence of vasospasm, pulmonary edema, or discontinuation of clazosentan treatment between the two groups were found over the treatment course, although refractory hyponatremia occurred less frequently in Group G than in Group NG (0% and 10.3%, p = 0.039, respectively). The incidence of diarrhea and the relative mucosal thickness was also significantly lower in Group G than in Group NG (7.3% and 21.9%; p = 0.0004, 113.8% vs. 175.4%; p = 0.001). Clazosentan combined with diuretics and Goreisan effectively reduced diarrhea and nasal mucosal swelling in patients with aSAH. This protocol may offer a viable approach for managing clazosentan-associated adverse events in aSAH patients.

Vasoplegic syndrome, a form of distributive shock that may manifest during or after cardiopulmonary bypass, is a serious complication that increases morbidity and mortality after cardiac surgery. No consensus definition exists, but vasoplegic syndrome is generally described as a state of pathologic vasodilation causing hypotension refractory to fluid resuscitation and vasopressor therapy, and resulting in organ malperfusion despite a normal or increased cardiac output. Diagnosis can be complex as there is a broad differential diagnosis for low systemic vascular resistance in the cardiac surgical patient. Interpretation of hemodynamic data can also be challenging in the setting of mixed shock states and mechanical support. This narrative review summarizes the pathophysiology of vasoplegic syndrome, the literature concerning its incidence and risk factors, the hemodynamic parameters important to the diagnosis of vasoplegic syndrome, a consensus definition of the syndrome, and a proposed goal-directed treatment framework.

Endothelin-1 is a potent vasoconstrictor that has diverse physiological functions in the kidney, including in the regulation of blood flow and glomerular filtration, electrolyte homeostasis and endothelial function. Overexpression of endothelin-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) that target the endothelin A (ETA) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ETA ERA, atrasentan, reduced albuminuria and kidney function decline. Concerns about the increased risks of fluid retention and heart failure with ERA use have led to the design of further trials to optimize dosing and patient selection. More recent studies have shown that the dual ETA receptor and angiotensin receptor blocker, sparsentan, preserved kidney function with minimal fluid retention in patients with IgA nephropathy. Moreover, combined administration of a low dose of the ETA-selective ERA, zibotentan, with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This Review describes our current understanding of the use of ERAs in patients with CKD to guide their optimal safe and effective use in clinical practice.

Cisplatin (DDP) is a commonly utilized chemotherapeutic agent. Nevertheless, the development of resistance to DDP significantly diminishes the effectiveness of DDP-based chemotherapy in patients with non-small cell lung cancer (NSCLC). In this study, we investigated the impact of endothelin 1 (EDN1) on the resistance to DDP in NSCLC.

The proliferation, invasion, and migration of NSCLC cells were detected by cell counting kit-8 and Transwell migration and invasion assays. ELISA was performed to analyze the inflammatory cytokines concentrations. The related protein levels of tumor necrosis factor (TNF) signaling pathway were analyzed by Western blot. Besides, a xenograft tumor mice model was established to explore the role of EDN1 in vivo.

The results showed that DDP-resistance upregulated EDN1 expression, cell viability, invasion, migration, and inflammation in NSCLC cells, while the results were reversed after EDN1 inhibition. EDN1 affected DDP-resistance of NSCLC by regulating TNF signaling pathway. Overexpression of TNF receptor-1 (TNFR1) reversed the decreased cell viability, invasion, migration, and inflammation induced by silencing EDN1 in A549/DDP cells. Moreover, silencing EDN1 inhibited tumor growth and the protein levels of EDN1 and TNFR1.

EDN1 promoted DDP resistance in NSCLC cells through the modulation of the TNF signaling pathway, suggesting a potential therapeutic intervention strategy for NSCLC.

Low testosterone in middle-aged/older men contributes to accelerated vascular aging, including endothelial dysfunction. However, the mechanisms by which low testosterone affects endothelial dysfunction are not well understood. We sought to determine whether higher endothelin-1 (ET-1) levels are associated with reduced brachial artery flow-mediated dilation (FMD) in middle-aged/older men with low testosterone. Plasma ET-1 was quantified in 60 men categorized as young (n = 20, age = 30 ± 4 yr, testosterone = 510 ± 63 ng/dL), middle-aged/older with normal testosterone (n = 20, age = 59 ± 6 yr, testosterone = 512 ± 115 ng/dL), or middle-aged/older with low testosterone (n = 20, age = 60 ± 8 yr, testosterone = 265 ± 47 ng/dL). Endothelial function was determined via brachial artery FMD. Venous and arterial endothelial cells were harvested via endovascular biopsy in a subset of participants and stained for ET-1 expression. Middle-aged/older men with normal testosterone exhibited lower brachial artery FMD (5.7 ± 2.2%) compared with young men (7.3 ± 1.3%, P = 0.020), which was exaggerated in middle-aged/older men with low testosterone (4.0 ± 1.8%, P = 0.010 vs. middle-aged/older men with normal testosterone). Plasma ET-1 was not different between young (5.6 ± 0.9 ng/dL) and middle-aged/older men with normal testosterone (6.0 ± 1.4 ng/dL, P = 0.681) but was higher in middle-aged/older men with low testosterone (7.7 ± 2.8 ng/dL) compared with both groups (P < 0.001 vs. young men; P = 0.013 vs. middle-aged/older men with normal testosterone). There was no difference in venous (P = 0.616) or arterial (P = 0.222) endothelial cell ET-1 expression between groups. There was a significant inverse association between plasma ET-1 and FMD (r =-0.371, P = 0.004). These data suggest that the accelerated age-associated reduction in endothelial dysfunction in middle-aged/older men with low testosterone is related to higher circulating ET-1.NEW & NOTEWORTHY Middle-aged/older men with low testosterone have reduced vascular endothelial function compared with young and age-matched men with normal testosterone. In this manuscript, we demonstrate that men with low testosterone have higher plasma endothelin-1, which is associated with worse brachial artery flow-mediated dilation. The source of higher plasma endothelin-1 remains unknown; however, higher circulating endothelin-1 appears to be a mechanism contributing to reduced vascular endothelial function in men with low testosterone.

Alcohol, in the form of ethyl alcohol or ethanol, is a widely consumed substance with significant implications for human health. Research studies indicate multifaceted effects of alcohol on the cardiovascular system with both protective and harmful effects on atherosclerotic cardiovascular disease (ASCVD), depending on the amount involved and the pattern of consumption. Among the critical components of the cardiovascular system are endothelial cells which line blood vessels. These cells are pivotal in maintaining vessel homeostasis, regulating blood flow, and preventing thrombosis. Their compromised function correlates with arterial disease progression and is predictive of cardiovascular events. Here we review research investigating how alcohol exposure affects the endothelium to gain insight into potential mechanisms mediating alcohol's influence on ASCVD underlying heart attacks and strokes. Studies highlight opposite effects of low versus high levels of alcohol on many endothelial functions. In general, low-to-moderate levels of alcohol (~5-25 mM) maintain the endothelium in a non-activated state supporting vascular homeostasis, while higher alcohol levels (≥50 mM) lead to endothelial dysfunction and promotes atherosclerosis. These biphasic endothelial effects of alcohol might underlie the varying impacts of different alcohol consumption patterns on ASCVD.

The carotid body (CB), the main peripheral arterial chemoreceptor, exhibits considerable structural and neurochemical plasticity in response to pathological conditions such as high blood pressure. Previous studies have shown that morphological alterations in the hypertensive CB are characterized by enlarged parenchyma due to cellular hypertrophy and hyperplasia, and vasodilation. To test whether hypertension can also induce neoangiogenesis and modulate its chemosensory function, we examined the immunohistochemical expression of two angiogenic factors, vascular endothelial growth factor (VEGF) and endothelin-1 (ET), and their corresponding receptors in the CB of adult spontaneously hypertensive rats (SHRs), and compared their expression patterns to that of age-matched normotensive Wistar rats (NWR). We found an increased VEGF-A and B, and VEGFR-2 expression in glomus and endothelial cells in the enlarged CB glomeruli of SHRs compared with that in NWR. Conversely, weaker immunoreactivity to VEGFR-1 was detected in cell clusters of the hypertensive CB. The expression of endothelin-converting enzyme 1 and its receptor ETA was higher in a subset of glomus cells in the normotensive CB, while the immunoreactivity to the ETB receptor was enhanced in endothelial cells of CB blood vessels in SHRs. The elevated endothelial expression of VEGF and ET-1 suggests their role as local vascular remodeling factors in the adaptation to hypertension, though their involvement in the cellular rearrangement and modulation of chemosensory function could also be implied.

Obstructive sleep apnea is associated with gestational hypertension. Elevated endothelin-1 is a proposed factor in the pathogenesis of gestational hypertension. However, the association between endothelin-1 and obstructive sleep apnea complicating pregnancy is unknown. In a prospective cohort of 60 pregnant patients with obesity but without confounding comorbid conditions (i.e. cardiac/pulmonary disease), plasma and placental samples were collected at delivery in 30 women with obstructive sleep apnea and 30 without. Endothelin-1 concentrations were evaluated using Western blot, quantitative real-time polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay. Multivariable analyses were conducted comparing endothelin-1 levels between obstructive sleep apnea and non-obstructive sleep apnea groups. There was no significant difference in band intensity or quantitative densitometric evaluation when comparing obstructive sleep apnea-positive and -negative groups (p = 0.42). mRNA expression of endothelin-1 did not differ in placental tissues between groups (p = 0.73). There was no significant difference in endothelin-1 median plasma concentrations between groups (p = 0.95). However, there was a significant sixfold increase in the rate of endothelin-1 elevation > 90th percentile (adjusted odds ratio 5.9, 95% confidence interval 1.05-32.7) after adjusting for confounding by body mass index. Additionally, lower pre-pregnancy body mass index (< 32 kg m-2) was associated with plasma endothelin-1 > 11 at delivery (p < 0.01), and class 3 obesity appeared protective for having elevated plasma endothelin-1 > 90th percentile (p = 0.03). Overall, in this prospective cohort of high-risk pregnant patients, obstructive sleep apnea was associated with an increased rate of markedly elevated (> 90th percentile) endothelin-1 plasma levels. Lower pre-pregnancy body mass index among patients with obesity was associated with elevated endothelin-1 plasma levels. Obstructive sleep apnea screening questionnaires focused on high body mass index may result in underestimated risk.

Hypertension is the leading cause of death globally, primarily due to its strong association with cardiovascular disease. The global prevalence of hypertension has surged over the past three decades, driven by rising rates of diabetes mellitus and obesity. Despite current antihypertensive therapies, only a small proportion of patients with hypertension achieve adequate blood pressure control, necessitating novel therapeutic strategies. In this Review we explore the challenges and emerging opportunities in hypertension management. Aprocitentan, a dual endothelin receptor antagonist, is the first agent from a novel class of antihypertensive drug to be licensed since 2007 and exemplifies innovative treatments on the horizon. Here we also address the complex factors contributing to poor hypertension control, including genetic influences, lifestyle factors, therapeutic inertia and poor patient adherence. We discuss the limitations of existing therapies and highlight promising new pharmacological approaches to hypertension management. Integrating these novel treatments alongside current pharmaceuticals combined with improved diagnostic and management strategies could substantially reduce the global burden of hypertension and associated cardiovascular disease.

Background Fasudil hydrochloride hydrate has been traditionally administered in the perioperative management of aneurysmal subarachnoid hemorrhage (aSAH) in Japan for the prevention of delayed cerebral ischemia (DCI) secondary to cerebral vasospasm. While clazosentan, a selective endothelin receptor antagonist, was introduced in April 2022 as an alternative therapeutic option for the same indication, comparative data regarding the therapeutic effectiveness between these agents remains limited. Therefore, this study investigated the differences in treatment outcomes between traditional fasudil hydrochloride hydrate and clazosentan in the perioperative management of aSAH. Materials and methods We retrospectively analyzed aSAH cases treated at our hospital from April 2020 to April 2024. Cases were stratified into either the conventional (fasudil hydrochloride hydrate) or clazosentan group. The primary endpoint was the frequency of DCI associated with cerebral vasospasm. The secondary endpoints were moderate or severe cerebral vasospasm within 14 days of aSAH onset, frequency of rescue therapy, modified Rankin scale (mRS) ≤3 at discharge and hospital stay duration. The postoperative incidence of symptomatic pulmonary edema and mortality assessed safety. Results The study analyzed 104 cases, 61 in the conventional group and 43 in the clazosentan group. The frequency of DCI did not differ between the conventional and clazosentan groups (three cases vs. one case, respectively). Similarly, no significant differences were observed in moderate or severe cerebral vasospasm, rescue therapy, or hospital stay duration. The conventional group had 29 cases with mRS ≤3 at discharge compared with 31 in the clazosentan group. A significantly higher incidence of symptomatic pulmonary edema was observed in the clazosentan group, with 15 cases vs. eight cases in the conventional group. No difference was observed in mortality at discharge. Conclusions We compared treatment outcomes between fasudil hydrochloride hydrate and clazosentan for aSAH. While clazosentan showed a non-significant trend toward lower DCI frequency, it was associated with increased symptomatic pulmonary edema. Given the study's limitations, larger-scale research with matched baseline characteristics is needed to definitively evaluate these agents' comparative efficacy.

Gills are the main respiratory organs of fish and bear important physiological and immunological functions, but the functional heterogeneity of interlamellar cell mass (ILCM) at the single-cell level has rarely been reported. Here, we identified 19 cell types from the gills of crucian carp (Carassius auratus) by single-cell RNA sequencing (scRNA-seq) in combination with histological analysis. We annotated ILCM and analyzed its functional heterogeneity at the single-cell level for the first time. Functional enrichment analysis and cell cycle analysis identified ILCM as a type of metabolically active cells in a state of constant proliferation, and identified the major pathways responsible for ILCM immunoregulation. Histological analysis revealed the morphology and positional relationships of 6 cell types. Meanwhile, the gene regulatory network of ILCM was established through weighted gene co-expression network analysis (WGCNA), and one transcription factor and five hub genes related to immunoregulation were identified. We found that pyroptosis might be an important pathway responsible for the immune response of ILCM. Our findings provide an insight into the physiological and immune functions of gills and ILCM at the single-cell level and lay a solid foundation for further exploration of the molecular mechanism of ILCM immunity functions.

Endothelin is a potent vasoconstrictor and contributes to the regulation of vascular perfusion. Aberrant endothelin-1 (ET-1) levels in aqueous humor have been reported across a variety of vascular diseases of the eye, including glaucoma. These findings suggest that dysregulation of ET-1 production may contribute to glaucoma pathophysiology. In this study, aqueous humor from patients undergoing ocular surgery was assayed for ET-1 abundance and related to the presence of glaucoma.

Open angle glaucoma patients (n=62 total) from the ophthalmology clinics of the University of Iowa Hospitals and Clinics were enrolled in this study and organized into three distinct cohorts based on their diagnostic criteria, including those with primary open angle glaucoma (POAG, n=25 patients), normal tension glaucoma (NTG, n=17 patients), exfoliation glaucoma (XFG, n=8 patients), and normal controls (n=12 patients).

Aqueous humor was collected intraoperatively from patients undergoing surgeries for glaucoma (including minimally invasive glaucoma surgeries, trabeculectomy, or glaucoma drainage device implantation) for samples in the glaucoma cohorts and cataract extraction for those in the control cohort. Aqueous humor was assayed by ELISA to measure and compare ET-1 abundance between the glaucoma cohorts and control cohort. ET-1 levels were also analyzed with linear regression to control for the covariates of age and sex.

ET-1 was significantly elevated in the aqueous humor of patients in the POAG (mean ± SD: 7.8 ± 5.1 pg/mL; p = 0.002) and NTG cohorts (6.1 ± 3.0 pg/mL; p = 0.030) compared to the control (4.0 ± 1.9 pg/mL). No significant difference in aqueous ET-1 was detected in the XFG cohort (6.2 ± 4.5 pg/mL; p = 0.230) compared to the control. Significantly higher ET-1 levels were detected in a merged grouping of all glaucoma cohorts (POAG, NTG, XFG) relative to controls (p = 0.021). Analysis of covariance indicated neither age nor sex was associated with ET-1 level (p = 0.60 and p = 0.27), respectively. Controlling for age and sex had minimal influence on the comparison of ET-1 levels in the POAG versus control cohort (p = 0.018) and nominal influence on the comparisons between the NTG (p = 0.089) or XFG cohort (p = 0.15) relative to the control.

Elevated ET-1 in aqueous humor was associated with POAG and NTG compared to controls amongst cohorts of patients at the University of Iowa. These data suggest that dysregulation of vascular perfusion may have a role in the pathophysiology of POAG. The analyses of NTG and XFG samples were limited by the relatively small sample sizes.

Vascular aging (VA) is a common etiology of various chronic diseases and represents a major public health concern. Intermittent hypoxia (IH) associated with obstructive sleep apnea-hypopnea syndrome (OSAHS) is a primary pathological and physiological driver of OSAHS-induced systemic complications. A substantial proportion of OSAHS patients, estimated to be between 40% and 80%, have comorbidities such as hypertension, heart failure, coronary artery disease, pulmonary hypertension, atrial fibrillation, aneurysm, and stroke, all of which are closely associated with VA. This review examines the molecular and cellular features common to both OSAHS and VA, highlighting decreased melatonin secretion, impaired autophagy, increased apoptosis, increased inflammation and pyroptosis, increased oxidative stress, accelerated telomere shortening, accelerated stem cell depletion, metabolic disorders, imbalanced protein homeostasis, epigenetic alterations, and dysregulated neurohormonal signaling. The accumulation and combination of these features may underlie the pathophysiological link between OSAHS and VA, but the exact mechanisms by which OSAHS affects VA may require further investigation. Taken together, these findings suggest that OSAHS may serve as a novel risk factor for VA and related vascular disorders, and that targeting these features may offer therapeutic potential to mitigate the vascular risks associated with OSAHS.

Background/Objectives: Alzheimer's disease (AD) and related dementias (ADRD) disproportionately impact racial and ethnic minorities. Contributing biological factors that explain this disparity have been elusive. Moreover, non-invasive biomarkers for early detection of AD are needed. Endothelin-1 (ET-1), a vasoconstrictive factor linked to cerebral vascular disease pathology and neuronal injury, could provide insights to better understand racial disparities in AD. As a potent vasoconstrictive peptide that regulates contractions in smooth muscle, endothelial cells, and pericytes, ET-1 may result in cerebral vascular constriction, leading to cerebral hypoperfusion; over time, this may result in neuronal injury, contributing to the pathology of AD. The role of the ET-1 system as a driver of ethnic disparities in AD requires further investigation. In the United States (U.S.), ET-1 dysregulation in Hispanic/Latinx (H/L) ethnic populations has largely been unexplored. Genetics linking ET-1 dysregulation and racial disparities in AD also require further investigation. In this study, we examined the role of the ET-1 protein in human plasma as a potential biomarker with predictive value for correlating with the development of AD by age, race, and sex. Methods: We examined ET-1 protein levels using quantitative mass spectrometry in AA and NHW patients with AD, along with controls. Results: A partial correlation between age at draw and ET-1, stratified by race and sex, while controlling for AD status, was significant for female AAs (r = 0.385, p = 0.016). When the data were not stratified but controlled for AD status, the partial correlation between age at draw and ET-1 was not significant (r = 0.108, p = 0.259). Conclusions: Based on the small number of plasma specimens and no plasma specimens from H/L individuals with AD, we conclude that ET-1 was clearly not a significant factor in predicting AD in this study and will require a larger scale study for validation.

In every hospital in Japan, until 2022, the primary treatment for preventing delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) involved a combination of ozagrel sodium (Oz), fasudil hydrochloride (Fs), cilostazol, and statins. However, with the approval of clazosentan in January 2022, it has been used as a first-choice drug more frequently. Despite this shift, limited evidence exists regarding the use of clazosentan as the first choice for DCI prevention. In this study, we analyzed the efficacy and outcomes of these two treatments in aSAH patients. Patients treated with Oz+Fs were enrolled between January 2014 and March 2022. In April 2022, clazosentan was prescribed to prevent DCI. Clinical data were collected, and propensity-score matching was conducted based on the clazosentan group. The primary endpoint was the functional outcome at discharge and 6-12 months after admission; the secondary endpoints were the incidence of cerebral vasospasm (CV) and DCI. In this study, 221 patients were included, and 27 were selected from both groups after matching. The incidence of CV was significantly lower in the clazosentan group (11.1% vs. 55.6%, p<0.01), and the incidence of DCI tended to be lower in the clazosentan group (3.7% vs. 25.9%, p=0.05). No significant difference was observed in the primary endpoint of functional outcome at discharge; however, a significant improvement in functional outcome was observed in the clazosentan group at 6 months (96.3% vs. 70.4%, p<0.05). Clazosentan significantly reduced the incidence of CV and improved functional outcomes in patients with aSAH compared to Oz+Fs.

Endothelin (ET)-1 contributes to melanoma progression via cell proliferation, invasion, and migration. We previously reported that annexin A2 (AnxA2) binds to ET receptors. In this study, we aimed to further investigate role of AnxA2 in melanoma cell proliferation after ET-1 stimulation. AnxA2 knockdown inhibited ET-1-stimulated cell proliferation and AKT activation in SK-MEL28 melanoma cells. ET-1 stimulation phosphorylated serine on AnxA2, and AnxA2 Ser25 phosphorylation-deficient mutant (AnxA2 S25A) cells showed lower ET-1-stimulated cell proliferation and AKT activation than the rescue AnxA2 knockdown (AnxA2 res) and AnxA2 Ser11 phosphorylation-deficient mutant (AnxA2 S11A) cells. Although AnxA2 S25A was localized to the plasma membrane, it exhibited lower colocalization with ET receptors than AnxA2 res and AnxA2 S11A on the plasma membrane. These results suggest that phosphorylation of AnxA2 Ser25 affects the colocalization of AnxA2 and ETRs and plays an important role in cell proliferation and AKT activation in ET-1 stimulated melanoma cells.

Despite advances in diabetes management, there is an urgent need for novel therapeutic strategies since the current treatments remain insufficient in halting the progression of diabetic nephropathy-diabetic kidney disease (DN-DKD). This review is mainly addressed on the pivotal role of endothelin-1 in the pathophysiology of DN, with a specific focus on its effects on podocytes and the glomerular filtration barrier. Endothelin-1 promotes mesangial cell proliferation, sclerosis, and direct podocyte injury via the activation of endothelin type A and B receptors, that drive the progression of glomerulosclerosis in DN-DKD. Endothelin receptor antagonists, including drugs like atrasentan and sparsentan, have demonstrated nephroprotective effects in experimental models by reducing proteinuria and podocyte injury. The therapeutic potential to slow the progression of DN to end-stage kidney disease (ESKD) of these endothelin receptor antagonists in clinical practice is currently under evaluation. However, fluid retention and increased risk of heart failure associated with endothelin receptor antagonists need careful consideration. This review aims to provide an in-depth analysis of the pathophysiological role of endothelin and the emerging therapeutic implications of targeting this pathway in DN-DKD and discusses efficacy, safety, and the possibility of combining the new generation of endothelin receptor antagonists with the standard treatment of CKD and DN-DKD.

The concept of multiple physiologic roles played by a single layer of endothelium on the intimal face of blood vessels started gaining recognition in the 1960s [...].

Hypoxic ischemic encephalopathy (HIE) refers to neonatal hypoxic brain injury caused by severe asphyxia during the perinatal period. With a high incidence rate and poor prognosis, HIE accounts for 2.4% of the global disease burden, imposing a heavy burden on families and society. Current clinical treatment for HIE primarily focuses on symptomatic management and supportive care. Therefore, the developments of effective treatment strategies and new drug formulations are critical for improving the prognosis of HIE patients. In order to protect the compromised neurovascular units after HIE, we prepared membrane-fused nanovesicles for delivering rapamycin and si EDN1 (TRCAM@RAPA@si EDN1). Due to the homotypic targeting feature of membrane-fused nanovesicles, we employed astrocyte membranes as synthetic materials to improve the targeting of astrocytes in brain while reducing the clearance of nanovesicles by circulatory system. Additionally, the surface of cell membrane was modified with CXCR3 receptors, enhancing the homing of nanovesicles to infarcted lesions. Lipid vesicles were modified with TK and RVG29 transmembrane peptides, enabling responsive release of internal drugs and blood-brain barrier penetration. Internally loaded rapamycin could promote protective autophagy in astrocytes, improve cellular oxidative stress, while si EDN1 could reduce the expression level of endothelin gene, thereby reducing secondary damage to neurovascular units.

Sickle cell disease (SCD) carries a significant risk for poor vascular health and vascular dysfunction. High levels of vascular reactive oxygen species (ROS) as well as elevated plasma endothelin-1 (ET-1), a potent vasoconstrictor with actions via the ETA receptor, are both common phenotypes in SCD. Alpha-1 adrenergic receptor activation is a major mediator of stress-induced vasoconstriction. However, the mechanism of the SCD enhanced vasoconstrictive response is unknown. We hypothesized that SCD induces enhanced alpha-1 adrenergic mediated vasoconstriction through the ET-1/ETA receptor pathway in arterial tissues. Utilizing humanized SCD (HbSS) and genetic control (HbAA) mice, alpha-1a, but not alpha-1b or alpha-1d, receptor expression was significantly greater in aortic tissue from HbSS mice compared to HbAA mice. Significantly enhanced vasoconstriction in aortic and carotid arterial segments were observed from HbSS mice compared with HbAA mice. Treatment with ambrisentan, a selective ETA receptor antagonist, and a ROS scavenger normalized the aortic vasoconstrictive response in HbSS mice. In a randomized translational study, patients with SCD were treated with placebo or ambrisentan for 3 months, with the treatment group showing an increase in the percent brachial arterial diameter. Taken together, these data suggest that the ETA receptor pathway interaction with the adrenergic receptor pathway contributes to enhanced aortic vasoconstriction in SCD. Findings indicate the potential of ETA antagonism as a therapeutic avenue for improving vascular health in SCD.

With age, lungs undergo typical changes that lead to a deterioration of respiratory function. Our aim was to assess the role of age-associated hyperphosphatemia in these changes.

We used C57BL6 mice to study an ageing model in vivo and human lung fibroblasts were treated with a phosphate donor, beta-glycerophosphate (BGP), to explore mechanisms involved. Respiratory function was registered with a double chamber plethysmograph. Lung structure was analysed by different staining, phosphate and cytokines levels by colorimeric kits, expression of fibrosis, inflammation and ET-1 system by western blot or RT-PCR.

Old mice showed hyperphosphatemia, along with lung fibrosis, loss of elastin, increased expression of pro-inflammatory cytokines and impaired respiratory function. BGP induced inflammation and fibrosis in fibroblasts through the activation and binding of NFkB to the MCP-1 or FN promoters. BGP increased ECE-1 expression by inducing NFkB binding to the ECE-1 promoter. QNZ, an NFkB inhibitor, blocked these effects. When ECE-1 was inhibited with phosphoramidon, BGP-induced inflammation and fibrosis were significantly reduced, suggesting a role for ET-1 in BGP-mediated effects.ET-1 produced effects similar to those of BGP, which were also dependent on NFkB. To study the pathophysiological relevance of hyperphosphatemia in vivo, a low-P diet was administered to a group of old animals, showing an improvement in fibrosis, inflammation and respiratory function compared to old mice on a standard diet.

These results suggest that age-related hyperphosphatemia induces inflammation, fibrosis, and impaired respiratory function in old mice; these effects appear to be mediated by ET-1 and NFkB activation.

To maintain homeostasis in the heart, endothelial cells and cardiomyocytes engage in dynamic cross-talk through paracrine signals that regulate both cardiac development and function. Here, we review the paracrine signals that endothelial cells release to regulate cardiomyocyte growth, hypertrophy and contractility, and the factors that cardiomyocytes release to influence angiogenesis and vascular tone. Dysregulated communication between these cell types can drive pathophysiology of disease, as seen in ischemia-reperfusion injury, diabetes, maladaptive hypertrophy, and chemotherapy-induced cardiotoxicity. Investingating the role of cross-talk is critical in developing an understanding of tissue homeostasis, regeneration, and disease pathogenesis, with the potential to identify novel targets for diagnostic and therapeutic purposes.

Endothelin-1 (ET-1), the most potent vasoconstrictor identified to date, contributes to cerebrovascular dysfunction. ET-1 levels in postmortem brain specimens from individuals diagnosed with Alzheimer's disease (AD) and related dementias (ADRD) were shown to be related to cerebral hypoxia and disease severity. ET-1-mediated vascular dysfunction and ensuing cognitive deficits have also been reported in experimental models of AD and ADRD. Moreover, studies also showed that ET-1 secreted from brain microvascular endothelial cells (BMVECs) can affect neurovascular unit integrity in an autocrine and paracrine manner. Vascular contributions to cognitive impairment and dementia (VCID) is a leading ADRD cause known to be free of neuronal tau pathology, a hallmark of AD. However, a recent study reported cytotoxic hyperphosphorylated tau (p-tau) accumulation, which fails to bind or stabilize microtubules in BMVECs in VCID. Thus, the study aimed to determine the impact of ET-1 on tau pathology, microtubule organization, and barrier function in BMVECs. Cells were stimulated with 1 μM ET-1 for 24 h in the presence/absence of ETA (BQ123; 20 μM) or ETB (BQ788; 20 μM) receptor antagonists. Cell lysates were assayed for an array of phosphorylation site-specific antibodies and microtubule organization/stabilization markers. ET-1 stimulation increased p-tau Thr231 but decreased p-tau Ser199, Ser262, Ser396, and Ser214 levels only in the presence of ETA or ETB antagonism. ET-1 also impaired barrier function in the presence of ETA antagonism. These novel findings suggest that (1) dysregulation of endothelial tau phosphorylation may contribute to cerebral microvascular dysfunction and (2) the ET system may be an early intervention target to prevent hyperphosphorylated tau-mediated disruption of BMVEC barrier function.

There is no study that has investigated the impact of exercise in a combined hypoxic and hot environment on endothelial function. Therefore, we tested whether aerobic exercise in a combined hypoxic and hot conditions induces further enhancement of endothelial function. Twelve healthy males cycled at a constant workload (50% of their maximal oxygen uptake under normoxic/thermoneutral conditions) for 30 min in four different environments: exercise under normoxic condition (NOR: fraction of inspiratory oxygen or FiO2 = 20.9%, 20°C), exercise under hypoxic condition (HYP: FiO2 = 14.5%, 20°C), exercise under hot condition (HOT: FiO2 = 20.9%, 30°C), and exercise under combined hypoxia and hot conditions (HH: FiO2 = 14.5%, 30°C). Before, during, and after exercise, cardiovascular variables (e.g., heart rate, blood flow, and shear rate), blood variables, and endothelial function evaluated by flow-mediated dilation (FMD) were assessed. Heart rates were significantly higher throughout the HH trial's experimental period than the other trials (p < 0.05). However, in the HH trial, brachial artery blood flow and shear rate did not differ from those in other trials after exercise. Plasma catecholamines (epinephrine, norepinephrine, and dopamine) elevations in response to exercise were significantly higher in the HH trial than in the other three trials (p < 0.05). No considerable differences were observed in FMD responses among trials before and after the exercise. In conclusion, aerobic exercise in a combined hot and hypoxic environment further activated sympathetic nervous activity but did not considerably enhance blood flow, shear rate, or endothelial function.

To evaluate the serum level of endothelin-1 (ET-1) and lipid profile in chronic periodontitis patients before and after periodontal therapy.

Sixty systemically healthy patients were divided into two groups, each with 30 patients. Group A with 30 healthy individuals and Group B with 30 chronic periodontitis patients. Group B was further divided into Group B1 and Group B2. Group B1 consisted of 15 patients with clinical attachment loss (CAL) of 1-2 mm treated by nonsurgical periodontal therapy. Group B2 of 15 patients with CAL of 3-4 mm, treated by periodontal flap surgery. Blood samples were collected before and 3 months following periodontal treatment to determine the serum level of ET-1 and lipid profile.

There was a statistically significant difference in ET-1 and lipid profile levels before and after periodontal treatment in both Groups B1and B2. However, the difference was more significant in Group B2 than Group B1 (P < 0.001).

Serum ET-1 and lipid profile could be a potential biomarker for periodontal and cardiovascular diseases. Periodontal therapy could reduce the risk of cardiovascular disease by reducing ET-1 and lipid profile postoperatively.

The morbidity of aneurysmal subarachnoid hemorrhage (aSAH) remains high, particularly because of secondary cerebral lesions that significantly aggravate the primary lesions. The main type of secondary lesions is delayed cerebral ischemia (DCI), in which platelets (PLT) appear to play a key role. Mean platelet volume (MPV) is an indirect marker of platelet activation. We aimed to determine the individual trajectories of MPV over time in patients with and without DCI during the course of aSAH. This is a single-center, retrospective, longitudinal analysis of individual trajectories of MPV over time, in a cohort of aSAH patients included in the Prospective, Observational Registry of Patient with Subarachnoid Hemorrhage in Neurocritical Care Unit (ProReSHA). A mixed-effects linear regression model was used to compare the trajectories of MPV and MPV/PLT ratio between patients who developed a DCI and those who did not. A total of 3634 MPV values were collected in 587 patients. The analysis of MPV as a function of DCI occurrence showed a significant difference in the trajectory over time between patients with DCI and those without, with an estimate of 0.02 (95%CI 0.01, 0.04, p = 0.009). The analysis of the MPV/PLT ratio as a function of DCI occurrence and other covariates showed a significant difference in the trajectory over time only for patients with a modified Fisher score less than 3, with an estimate of -0.59 (95%CI: -0.94, -0.23, p = 0.001). The individual trajectories of MPV over time differ between patients with DCI and those without. However, MPV values vary greatly over time and between patients. Thus it does not appear as a reliable biomarker for stratifying patients based on their specific risk of developing DCI. ClinicalTrials.gov identifier: (NCT02890004), registered in August 2016.

The endothelial cells of the blood circulation are exposed to hemodynamic forces, such as cyclic strain, hydrostatic forces, and shear stress caused by the blood fluid's frictional force. Endothelial cells perceive mechanical forces via mechanosensors and thus elicit physiological reactions such as alterations in vessel width. The mechanosensors considered comprise ion channels, structures linked to the plasma membrane, cytoskeletal spectrin scaffold, mechanoreceptors, and junctional proteins. This review focuses on endothelial mechanosensors and how they alter the vascular functions of endothelial cells. The current state of knowledge on the dysregulation of endothelial mechanosensitivity in disease is briefly presented. The interplay in mechanical perception between endothelial cells and vascular smooth muscle cells is briefly outlined. Finally, future research avenues are highlighted, which are necessary to overcome existing limitations.