Endothelin-1

Activin A-Endothelin-1 Axis Governs Pulmonary Vascular Remodeling: Mechanistic Basis for Emerging Therapies in PAH.

Novia Nurul Faizah, Gusty Rizky Teguh Ryanto, Sagita Mega Sekar Kencana +4 more

Pulmonary arterial hypertension remains a life-threatening disease despite advances in vasodilator therapy. Vascular remodeling, partly driven by pulmonary artery endothelial cell dysfunction, is accompanied by vasoactive mediators imbalance such as ET-1 (endothelin-1). Although endothelin receptor antagonists alleviate vasoconstriction, they incompletely address the remodeling process. We previously reported how endothelial-derived activin A promotes vascular remodeling, leading to the clinical development of the activin signaling inhibitor sotatercept, which improves outcomes when added to endothelin receptor antagonists. As both activin A and ET-1 originate from endothelial cells and promote remodeling, we investigated whether activin A regulates ET-1 production and activity in pulmonary arterial hypertension.

Effects of a sea level stay on pulmonary hemodynamics in patients with pulmonary arterial hypertension living in Quito near 2850m.

Silvia Ulrich, Julian Müller, Michael Furian +11 more

Amongst the >80 Mio people living >2500m are patients with pulmonary arterial hypertension (PAH).

A KCa 2.2/2.3 Opener Reverses ET-1-Induced NLRP3 Activation in Hypertensive Mice Corpora Cavernosa.

Rafael Sobrano Fais, Simon Gabriel Comerma-Steffensen, Estefano Pinilla +4 more

Hypertension-induced erectile dysfunction is associated with endothelial dysfunction in the corpus cavernosum. Membrane depolarization activates the NLRP3 inflammasome, with downregulation of endothelial Ca2+-activated K+ channels type 2.3 (KCa 2.3) and upregulation of endothelin-1 (ET-1) linked to erectile dysfunction. However, underlying mechanisms remain incompletely understood. We hypothesized that activating KCa 2.2/2.3 channels reverses erectile dysfunction and ET-1-induced NLRP3 activation in hypertensive DOCA/salt mice. Hypertension was induced in mice using a DOCA/salt model, with unilaterally nephrectomized mice as controls. We measured blood pressure, intracavernous pressure (ICP), and corpus cavernosum (CC) contractility, and performed immunoblots for KCa 2.3, caspase-1, and interleukin-1β (IL-1β). DOCA/salt mice showed impaired erectile function and increased IL-1β activity and reduced KCa 2.3 expression. Treatment with the endothelin receptor antagonist bosentan or the KCa 2.2/2.3 channel opener NS13001 reversed these dysfunctions and reduced ET-1-induced NLRP3 activation. NS13001 also restored decreased currents in endothelial cells exposed to ET-1. These findings establish that hypertension-induced erectile dysfunction involves an ET-1/membrane depolarization/NLRP3 inflammasome axis in corpus cavernosum endothelial cells, and that targeting endothelial KCa 2.2/2.3 channels represents a promising therapeutic strategy to counteract erectile dysfunction.

Disproportionality analysis of adverse events associated with endothelin receptor antagonists based on the FDA adverse event reporting system (FAERS).

Lizhu Han, Sitian Li, Jianting Liao +5 more

Endothelin receptor antagonists (ERAs), including bosentan, ambrisentan, and macitentan, are recognized as first-line treatments for pulmonary arterial hypertension (PAH). Although their therapeutic efficacy is well established, variations in receptor selectivity and metabolic pathways may lead to distinct adverse drug event (ADE) profiles. Nonetheless, large-scale, real-world comparative safety data remain limited. As part of routine pharmacovigilance activities, we analyzed data from the U.S. Food and Drug Administration's Adverse Event Reporting System (FAERS) to identify disproportionate reporting signals.

Loss of endothelin-2 in pulmonary neuroendocrine cells promotes the development of hypoxia-induced pulmonary hypertension.

Yoko Suzuki, Risa Ramadhiani, Gusty Rizky Teguh Ryanto +8 more

Pulmonary hypertension (PH) encompasses a clinical spectrum of diseases with high morbidity and poor survival rates. Over the decades, many studies have reported that endothelin-1 (Edn1) plays a role in several subtypes of PH. However, the beneficial effects of its targeted drugs are only found in patients with group 1 pulmonary arterial hypertension but not in group 3 PH, which is related to lung diseases and hypoxia. In the present study, we revealed contrasting findings for Edn1 and its highly similar peptide endothelin-2 (Edn2) in hypoxia-induced PH. Edn2 expression exhibited a distinct and transient pattern under hypoxic conditions. Moreover, epithelial cell-specific Edn2-knockout mice showed exacerbated PH phenotypes compared with wild-type mice. We further demonstrated that acute changes in oxygen levels, but not the low-oxygen condition, were pivotal for Edn2 expression regulation, suggesting that Edn2 is involved in oxygen sensing. Supporting these findings, the specific deletion of Edn2 in sensory-specialised lung cells called pulmonary neuroendocrine cells led to an exacerbated PH phenotype. In conclusion, our study revealed a previously unknown protective role of Edn2 in the development of hypoxia-induced PH. Owing to the contradictory findings between Edn1 and Edn2 in the pathogenesis of lung diseases, careful consideration is required when using endothelin receptor antagonists for PH associated with lung disease and hypoxia.

Updates in the Treatment of Pediatric Pulmonary Arterial Hypertension.

Danya Z Jafri, James M Beck, Samantha A Kaplan +8 more

Pediatric pulmonary arterial hypertension (PAH) is a relentless and potentially fatal disease marked by elevated pulmonary vascular resistance and pulmonary pressure as a result of unchecked vascular remodeling, proliferation, and dysfunction. While pharmacological treatment algorithms for adult PAH are well-established and frequently updated, pediatric PAH treatment guidelines in the United States are generally based on limited clinical trials and expert opinion, leaving clinicians to extrapolate from adult data and expert consensus rather than pediatric-specific, evidence-based protocols. Endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin-pathway agents remain the therapeutic cornerstone, yet clinical practice is being reshaped by pivotal therapeutic developments. Recent advances highlight differences in monotherapy versus combination pharmacological regimens, alongside active trials investigating interventional/surgical procedures in the amelioration of long-term outcomes. This review seeks to consolidate contemporary data and clinical trial highlights to reflect a necessary shift toward precise, developmentally informed pharmacotherapy in children, underscoring the pressing need for an updated pharmacological guideline that incorporates pediatric-specific trials and harmonizes labeling and long-term safety surveillance in the treatment of pediatric PAH.

Efficacy and Safety of Oral Treprostinil in Patients with Pulmonary Arterial Hypertension on Background Monotherapy or Dual Therapy.

Daniel Lachant, Amresh Raina, Mrinalini Krishnan +10 more

Pulmonary arterial hypertension (PAH) is a progressive, often fatal disease characterized by an elevation in pulmonary arterial pressure and pulmonary vascular resistance (PVR). Oral treprostinil is indicated for the treatment of PAH and has been shown to delay disease progression and to improve exercise capacity.

Real-world observational study on pulmonary arterial hypertension: Italian cohort treated with macitentan and/or selexipag as a part of a combination treatment (INSPECTIO).

Michele D'Alto, Laura Scelsi, Livio Giuliani +17 more

Pulmonary arterial hypertension (PAH) is a progressive disease associated with significant morbidity and mortality. Combination therapy targeting multiple pathways has been shown to improve clinical outcomes.

Epigenetic Drivers of Pulmonary Hypertension: Environment Meets Genome.

William N Whitley, Richard M Millis

Pulmonary hypertension (PH) is a progressive disease in which the pulmonary arteries thicken and narrow, raising pulmonary vascular resistance (PVR) and eventually straining the right ventricle. Known gene mutations explain only a minority of cases and often do not account for why the disease starts, worsens, or varies so widely between patients. Growing evidence suggests that epigenetic changes, chemical marks on DNA and its packaging that alter how genes are used without changing the DNA sequence, help explain this gap. These changes, including DNA methylation, histone modification, and non-coding RNAs, can be triggered by common exposures and disease states, and they can produce lasting shifts in vascular, immune, and metabolic pathways. This narrative review synthesizes current data showing how intrinsic stresses (mitochondrial dysfunction, oxidative stress, and cancer-like metabolic reprogramming) interact with extrinsic and often modifiable factors. Obesity, cigarette smoke, asbestos exposure, chronic hypoxia, and systemic inflammation drive PH through epigenetic reprogramming. We highlight major molecular hubs implicated across studies, including bone morphogenetic factor receptor 2 (BMPR2), NOTCH3, endothelin-1 (ET-1), transforming growth factor‑β (TGF-β), interleukin‑6 (IL-6), and CCL5, and we summarize emerging therapeutic approaches aimed at epigenetic regulators and microRNA networks. This narrative review was not conducted under Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and does not constitute a formal systematic review. The information in this review provides a practical framework for clinicians and researchers to improve risk assessments, to employ biomarkers, and to develop therapies that go beyond vasodilation to address upstream drivers of pulmonary arterial remodeling. This framework may also serve as a model for other difficult-to-treat diseases in which incomplete genetic explanations and limited attention to environmental exposures have slowed progress in prevention, early detection, and personalized treatment.

Treatment Patterns in Patients With Incident Pulmonary Hypertension: Real-World Data From the Pulmonary Hypertension Association Registry.

Sarah L Khan, Carly J Paoli, Noah Kime +6 more

Current evidence supports risk-based treatment for pulmonary arterial hypertension (PAH) with an endothelin receptor antagonist and phosphodiesterase type 5 inhibitor as initial therapy for patients with low- and intermediate-risk PAH, and triple therapy with the addition of a parenteral prostacyclin for patients with high-risk PAH.

Endothelin-1 in the failing Fontan: pathobiology, precision therapeutics, and future trial design.

Iman Maiza

The Fontan circulation, devised as definitive palliation for single-ventricle congenital heart disease, imposes systemic venous hypertension, loss of pulmonary arterial pulsatility, and restricted preload reserve. These hemodynamic trade-offs progressively injure the pulmonary vasculature, liver, and lymphatic system, producing late morbidities including elevated pulmonary vascular resistance, Fontan-associated liver disease (FALD), protein-losing enteropathy, and arrhythmias. Endothelin-1 (ET-1), a potent vasoconstrictor and profibrotic mediator, plausibly unifies these complications. Mechanistic studies demonstrate ET-1 upregulation in failed Fontan lungs, activating PLC-Ca2+, RhoA/ROCK, and MAPK/ERK cascades to drive vasoconstriction and remodeling. In cirrhotic livers, ET-1 localizes to stellate cells, promoting contraction and fibrogenesis, mechanisms biologically relevant to congestive FALD. Clinical cohorts consistently show elevated ET-1 correlating with hospitalization, exercise intolerance, and arrhythmias. Trials of endothelin-receptor antagonists (bosentan, ambrisentan, macitentan) demonstrate reassuring safety and suggest benefit when outcomes emphasize ventilatory efficiency or hepatic endpoints rather than peak oxygen consumption, which is physiologically constrained in Fontan physiology. Given the mixed results of existing trials, a framework is outlined that stratifies Fontan patients into pulmonary-inefficiency, congestive-hepatic, lymphatic, and arrhythmia-dominant phenotypes, using co-primary endpoints such as VE/VCO2 slope, elastography, and biomarker panels. By linking ET-1 biology to pragmatic trial design, this approach emphasizes targeted strategies that may stabilize the circulation, extend transplant candidacy, and improve long-term outcomes.

Perinatal High-Fat Diet Induces Vascular Hypercontractility via DNA Hypomethylation of Endothelin Receptors and PKC-LTCC Axis Activation in Male Offspring.

Qiutong Zheng, Huamei Jian, Qinyuan He +4 more

Excessive fat intake is a well-established risk for hypertension; perinatal nutritional imbalances could increase vascular risks, but underlying mechanisms remain unclear. Endothelin-1 (ET-1), a potent vasoconstrictor, is implicated in cardiovascular diseases. This study aimed to address this gap by investigating ET-1 receptor-mediated pathways with high-fat-diet (HFD) during pregnancy and lactation. Vascular function, Ca2 + signaling, molecular expression, and DNA methylation were assessed in mesenteric arteries (MA) of offspring. HFD offspring exhibited increased fetal/adult weight, thickened MA wall, and enhanced ET-1-mediated vasoconstriction. Mechanistically, perinatal HFD upregulated ET-1 receptors (ETAR/ETBR) via hypomethylation of their gene promoters (Ednra/Ednrb), which augmented ET-1-induced Ca2 + currents, fluorescence Ca2 + transients, and vascular tone. Which relied on the PKC-LTCC axis (strengthened by PKC activator and LTCC agonist) and altered intracellular Ca2 + handling (via ryanodine receptors and sarcoplasmic/endoplasmic reticulum Ca2 +-ATPase), but were independent of IP3 receptors. ETAR/ETBR blockers attenuated the hypercontractility, confirming receptor-mediated effects. This is the first study to reveal that perinatal HFD persistently enhances vascular re-activity via DNA hypomethylation of ET receptors and PKC-LTCC axis. These findings not only reveal a mechanism linking perinatal HFD to adult vascular hypercontractility but also highlight ET receptors and DNA methylation as potential targets for early intervention of developmental origins of cardiovascular disease.

Selection of Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension: A Comprehensive Narrative Review.

Naomi G Habib, Ankita Adhia, David Lopez +2 more

One of the major mechanisms in the pathogenesis of pulmonary arterial hypertension (PAH) is mediated by elevated levels of endothelin (ET)-1, which activates both ETA and ETB receptors in the pulmonary vasculature. Endothelin receptor antagonists (ERAs) are established treatments for PAH, and three agents-bosentan, ambrisentan, and macitentan-are approved for use in adults in the USA. All are orthosteric antagonists of ET-1 and bind with high affinity to the ETA receptor, which is found largely on vascular smooth muscle cells (SMCs) and involved in vasoconstriction. Bosentan and macitentan also bind to the ETB receptor, which is upregulated on SMCs and downregulated on endothelial cells in PAH, resulting in vasoconstriction, cell proliferation, and vascular remodeling. Studies show all three ERAs are efficacious in treating PAH as monotherapy or in combination with other PAH drugs and are generally well tolerated, but all can cause fetal harm and are contraindicated in pregnancy. However, there are no head-to-head clinical trials providing a comprehensive comparison of the overall efficacy and safety of ERAs in PAH. Consequently, we examined the literature on ERAs in PAH through a targeted search of the PubMed/MEDLINE database. This narrative review explores the role of ET-1 in PAH underlying the rationale for ET receptor antagonism. It also discusses the differing physicochemical and pharmacokinetic properties of each ERA and how these unique characteristics influence their receptor binding and kinetics, mechanisms of action, therapeutic effects, dosing frequency, and safety in PAH. In the absence of head-to-head clinical trials assessing their comparative efficacy and safety, it is important to understand both the similarities and the distinguishing characteristics of the three ERAs approved in PAH, to inform individualized treatment selection.

Genetic Syndromes and Multimorbidity in Adults with Congenital Heart Disease and Heart Failure: Insights from the PATHFINDER-CHD Registry.

Ann-Sophie Kaemmerer-Suleiman, Fritz Mellert, Stephan Achenbach +25 more

Background/Objectives: Progress in diagnostic and therapeutic strategies has resulted in an increasing prevalence of adults with congenital heart disease (ACHD), including those involving genetically determined syndromes. This study aimed to characterize prevalence, congenital phenotypes, heart failure (HF) stages, comorbidity burden, and current medical management of ACHD and concomitant genetically determined syndromes enrolled in a prospective HF-focused registry. Methods: The PATHFINDER-CHD Registry is a German-based (est. 2022) multicenter observational registry. This web-based platform consecutively tracks ACHD patients across the heart failure spectrum, including those with current or prior HF, as well as those at high structural or functional risk. HF stage was classified using a modified ACC/AHA scheme adapted for CHD; functional capacity was graded according to the Perloff classification. Baseline demographics, CHD anatomy, prior surgical/interventional treatment, cardiac and extracardiac comorbidities, and medication were collected from medical records. Results: Among 1987 enrolled ACHD, 107 (5.4%) had a genetic syndrome (n = 65, 60.7% women; mean age 33.5 ± 9.4 years; range 18-68). Most common syndromes were trisomy 21 (n = 49; 45.8%) and 22q11.2 deletion (n = 27; 25.2%); 31 patients (30.0) had rarer syndromes. Predominant CHD diagnoses were atrioventricular septal defect (n = 42, 39.3%), tetralogy of Fallot (n = 19, 17.8%), and pulmonary atresia with ventricular septal defect (n = 7, 6.5%). A systemic left ventricle was present in 102 (95.3%); 40 (37.4%) had primarily cyanotic CHD, and 7 (6.5%) an Eisenmenger physiology. Most patients (n = 71; 66.4%) had undergone definite surgical repair; 25 patients (23.3%) had at least one catheter intervention, including transcatheter valve implantation in 17 cases (15.9%). HF stage was mainly B (n = 30, 28.0%) or C (n = 75, 70.1%). Perloff functional class I/II was present in 97 (90.7%). Leading cardiac comorbidities included intrinsic aortopathy (n = 49, 45.8%), pulmonary arterial hypertension (n = 12, 11.2%), and arrhythmias (n = 10, 9.3%). Frequent extracardiac comorbidities were thyroid dysfunction (n = 34, 31.8%), kidney disease (n = 16, 15.0%), hyperuricemia (n = 13, 12.1%), and depression (n = 15, 14.0%). Pharmacotherapy was used in 66 patients (61.7%). Beta-blockers (n = 25, 23.4%) were common, while ACEi/ARB (n = 9, 8.4%), diuretics (n = 10, 9.3%), MRAs (n = 8, 7.5%), and SGLT2 inhibitors (n = 3; 2.8%) were infrequently prescribed; no patient received ARNI or digitalis. For targeted treatment of pulmonary arterial hypertension, phosphodiesterase-5 inhibitors (n = 7, 6.5%), endothelin receptor antagonists (n = 6, 5.6%), or prostacyclin analogues (n = 1, 0.9%) were used. As oral anticoagulants, vitamin K antagonists or direct oral anticoagulants (DOACs) were prescribed in 17 cases (15.9%). Forty-one patients (38.3%) received thyroid hormone replacement. Conclusions: Syndromic ACHD constitute a small but clinically high-risk subgroup within an HF-oriented registry, marked by complex CHD, substantial cardio-extracardiac multimorbidity (notably aortopathy, PAH, thyroid disease, renal dysfunction, depression), and low utilization of contemporary HF therapies. These data support specialized, interdisciplinary, longitudinal care pathways and prospective studies addressing outcomes and evidence-based HF management in syndromic ACHD.

Development of a Robust, Rapid and Reliable Tandem Mass Spectrometry Method for the Measurement of Sildenafil, Bosentan and their Major Metabolites.

Mohammad Ahmad Bik, Duygu Eryavuz Onmaz, Karam Mazin Kamil Gharab +4 more

Pulmonary arterial hypertension (PAH) is a lethal, progressive disease with a complex pathogenesis. Bosentan, a dual endothelin receptor antagonist, and sildenafil, a phosphodiesterase type 5 inhibitor, are used to treat PAH. In this study, we aimed to develop a liquid chromatography-tandem mass spectrometry method (LC-MS/MS) to measure the levels of bosentan, sildenafil, and their active metabolites in patients with PAH. We have developed an LC-MS/MS measurement procedure using a liquid-liquid extraction to measure serum drug concentrations and validated the procedure according to Clinical and Laboratory Standards Institute (CLSI) protocols. Finally, the validated method was used to measure the levels of sildenafil, bosentan, and their metabolite in pediatric PAH patients. The method was linear in the range of 0.975-1000 ng/ml and 0.76-3125 ng/ml for sildenafil and bosentan, respectively. LOQ values of sildenafil and bosentan were determined as 1.95 and 1.50 ng/ml, respectively. A method for measuring the levels of sildenafil and bosentan was developed that is rapid, robust, inexpensive, and requires a small serum volume. In addition, the validated method measured these drugs' levels and metabolites in pediatric patients with PAH. The results show that the established method can routinely monitor drug levels.

Influence of the angiotensin-(1-7) on the vascular effects of the endothelin-1 in normotensive and hypertensive rats.

Jaqueline Moura da Costa, Amanda de Sá Martins de Bessa, Lara Marques Naves +4 more

Angiotensin-(1-7) [Ang-(1-7)] exerts cardioprotective effects through Mas receptor activation. Endothelin-1 (ET-1) is implicated in cardiovascular pathologies. Previous studies indicate a cross-talk between angiotensin and endothelin pathways; however, it remains unclear whether Ang-(1-7) differentially modulates vascular responses to ET-1 in normotensive and hypertensive conditions. This study investigated the influence of Ang-(1-7) on ET-1-induced pressor and vascular responses in normotensive and hypertensive rats (SHR). Blood pressure was recorded in conscious animals. Vascular reactivity was assessed in isolated aortic rings, and coronary effects were assessed in isolated hearts using the Langendorff technique. ET-1 increased blood pressure and reduced heart rate only in Wistar rats, effects abolished by Ang-(1-7). In normotensive rats, Ang-(1-7) potentiated ET-1-induced vasoconstriction in endothelium-intact aortas independently of Mas receptors, but had no effect in the aorta without endothelium. In hypertensive rats, Ang-(1-7) attenuated ET-1 responses in endothelium-intact aorta via Mas receptor, whereas in endothelium-denuded vessels it potentiated the vasoconstriction. In isolated hearts, ET-1 produced a biphasic response in normotensive rats (vasodilation followed by vasoconstriction) but only vasoconstriction in hypertensive rats. Ang-(1-7) potentiated vasoconstriction in normotensive but attenuated it in hypertensive hearts, which was abolished by Mas receptor blockade. These findings demonstrate that Ang-(1-7) differentially modulates ET-1 actions in normotensive and hypertensive conditions, reinforcing RAS-endothelin cross-talk. Its counter-regulatory effect in hypertension highlights Ang-(1-7) as a promising therapeutic target in cardiovascular disease.

Ambrisentan for Early-Stage Low-Risk Pulmonary Arterial Hypertension: Design of the Randomized, Double-Blind, Placebo-Controlled ALEPH Trial.

Jun-Yan Kan, Xiao-Juan Zhang, Wan-de Yu +9 more

Early-stage pulmonary arterial hypertension (PAH) with mild hemodynamic abnormalities is increasingly being concerned because of the revised PAH definition. However, there is a lack of randomized controlled trials evaluating the efficacy of currently available medications in this population.

Exploring the relationship between adherence and outcomes in pulmonary arterial hypertension: A retrospective cohort study in the United States.

Teresa De Marco, Carly J Paoli, Hayley D Germack +6 more

Pulmonary arterial hypertension (PAH) is a rare, progressive disease with significant morbidity and mortality. New medications have improved outcomes, but adherence is crucial.

Sotatercept in Pulmonary Arterial Hypertension: Molecular Mechanisms, Clinical Evidence, and Emerging Role in Reverse Remodelling.

Ioan Tilea, Dragos-Gabriel Iancu, Ovidiu Fira-Mladinescu +2 more

Pulmonary arterial hypertension (PAH) is a severe, progressive vasculopathy characterized by endothelial dysfunction, medial hypertrophy, and maladaptive vascular and cardiac remodelling that ultimately leads to right-heart failure and premature death. Despite advances in vasodilator therapies targeting endothelin, nitric oxide, and prostacyclin pathways, a substantial proportion of patients fail to achieve or maintain a low-risk profile, highlighting the need for disease-modifying strategies. Dysregulation of transforming growth factor-β (TGF-β) superfamily signalling, with excessive activin and growth differentiation factor activity and impaired bone morphogenetic protein signalling, plays a central role in PAH pathobiology. Sotatercept, a first-in-class activin signalling inhibitor, restores this imbalance by selectively trapping pro-proliferative ligands, thereby addressing a key molecular driver of pulmonary vascular remodelling. Evidence from pivotal phase II and III trials-PULSAR, STELLAR, ZENITH, and HYPERION-demonstrates that sotatercept significantly improves exercise capacity, haemodynamics, and risk status when added to background therapy. This review summarises the molecular mechanisms underlying sotatercept's therapeutic effects, synthesises the current clinical evidence, and discusses its emerging role as a disease-modifying agent capable of promoting reverse pulmonary vascular remodelling within contemporary PAH management.

Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: Current Therapeutic Strategies and Future Prospects.

Yukina Mizuno Yokoyama, Ryu Watanabe, Tomohiro Yamaguchi +8 more

Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a severe form of pulmonary hypertension with poor prognosis. It most commonly arises in systemic sclerosis (SSc), followed by systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD). Its pathogenesis involves a complex interplay of immune dysregulation, chronic inflammation, endothelial injury, vascular remodeling, and fibrosis. Although vasodilators targeting the endothelin, nitric oxide, and prostacyclin pathways remain the therapeutic backbone, newer agents-including the activin signal inhibitor sotatercept and inhaled treprostinil-have expanded treatment options. Immune-targeted therapies such as glucocorticoids, cyclophosphamide, mycophenolate mofetil, rituximab, and IL-6 receptor inhibitors may benefit inflammation-dominant PAH phenotypes, while fibrotic phenotypes continue to demonstrate limited responsiveness. In addition to brain natriuretic peptide (BNP), N-terminal (NT)-proBNP and disease-specific autoantibodies, emerging biomarkers show promise for early detection, risk stratification, and personalized treatment, though validation in CTD-PAH is lacking. Advances in animal models replicating immune-mediated vascular injury and fibrosis have further improved mechanistic understanding. Despite these developments, substantial unmet needs remain, including the absence of disease-specific therapeutic strategies, limited biomarker integration into clinical practice, and a scarcity of large, well-designed trials targeting individual CTD subtypes. Addressing these gaps will be essential for improving prognosis in patients with CTD-PAH.

Hypoxic microenvironment and pulmonary hypertension.

Tiantian Mu, Boshuo Guo, Chuqi Xiang +4 more

Pulmonary hypertension (PH) is a serious pulmonary vascular disease characterized by a progressive increase in pulmonary vascular resistance and abnormally high pulmonary arterial pressure. The hypoxic microenvironment plays an important role in its development. Studies have indicated that early exposure of pulmonary vasculature to hypoxia in the hypoxic microenvironment triggers an adaptive response in the organisms and has a homeostatic regulatory effect. However, under prolonged hypoxic stimulation, pulmonary artery smooth muscle cells (PASMCs) and pulmonary artery endothelial cells (PAECs) can be induced to abnormally proliferate and migrate through endothelial cell dysfunction and endothelial-mesenchymal transition. This leads to irreversible pulmonary vascular remodeling, which ultimately results in PH formation. Core components of the hypoxic microenvironment include hypoxia-inducible factors (HIFs) through a complex regulatory network, metabolic reprogramming in the microenvironment (glucose metabolism, lipid metabolism, and amino acid metabolism), an overabundance of reactive oxygen species and redox imbalance, reprogramming of the immuno-inflammatory microenvironment, regulation of cell death patterns (apoptosis resistance, iron death, and autophagy imbalance), mechanical stress and cytoskeletal dynamics, non-coding RNA regulatory networks (miRNA, IncRNA, and circRNA), microbial-host interactions (gut flora metabolites), epigenetic regulation (DNA methylation, histone modification, and RNA modification) and Transient Receptor Potential (TRP) Channels and Calcium Signaling Regulation. These processes are interconnected in the organisms to induce or promote aberrant proliferation and migration of PASMCs and PAECs, which are the pathogenic mechanisms resulting in PH. Current clinical treatments for PH include endothelin receptor antagonists, drugs targeting cyclic guanosine monophosphate production, phosphodiesterase-5 inhibitors, and prostacyclin analogs. However, novel targeted drugs against HIF-1ɑ remain under development. Oxygen therapy and mechanical ventilation, gene therapy, and molecularly targeted interventions (modulation of the RhoA/ROCK pathway or non-coding RNAs) can improve hypoxemia. Future studies must integrate multi-omics data, incorporate artificial intelligence to accelerate drug development, and focus on gender and individualization to achieve precision therapy. In conclusion, an in-depth analysis of the mechanism of the hypoxic microenvironment in PH will provide the fundamental basis for developing more effective therapeutic strategies.

Macitentan and phosphodiesterase-5 inhibitor alone or in combination in newly diagnosed pulmonary arterial hypertension: a pooled analysis.

Vallerie V McLaughlin, Nicolas Sauvageot, Brian Hennessy +8 more

Upfront combination therapy with endothelin receptor antagonist (ERA) and phosphodiesterase-5 inhibitor (PDE5i) is guideline-recommended for low- or intermediate-risk pulmonary arterial hypertension (PAH). This study compared time to all-cause mortality for macitentan+PDE5i combination and each monotherapy.

Safety and efficacy of upfront triple therapy including parenteral treprostinil compared to double oral therapy in PAH (TripleTRE): study protocol for a randomised trial.

Olivier Sitbon, Gergely Agoston, Roberto Badagliacca +16 more

Pulmonary arterial hypertension (PAH) requires a complex and multidisciplinary care approach with regular follow-up visits to monitor disease progression and adaptation of treatment regimens. Current ESC/ERS Guidelines recommend initial double oral treatment (endothelin-receptor antagonist + phosphodiesterase type 5 inhibitor) in patients presenting at diagnosis with intermediate risk according to the three-strata risk score. Retrospective data analyses indicate a clinical benefit for upfront triple combination therapy including parenteral prostacyclins (PCA) in intermediate and high-risk patients. The multicentric TripleTRE trial aims to investigate the effect of initial triple combination therapy including parenteral PCA on risk status, compared to double oral in a prospective setting in patients at intermediate-high risk at diagnosis according to the four-strata risk score.

Topics in Lung Disease: Pulmonary Hypertension.

Alexander Kaysin, Sunil Swami, Oluwatoni Aluko +1 more

Pulmonary hypertension is a complex progressive disorder characterized by elevated pulmonary artery pressure. Diagnosis requires early clinical suspicion based on symptoms such as exertional dyspnea, fatigue, syncope, and chest discomfort, with echocardiography as a first-line diagnostic study. Diagnosis is confirmed using right heart catheterization, with a mean pulmonary artery pressure of 20 mm Hg or more and pulmonary vascular resistance greater than 2 Wood units. Strategies for primary and secondary prevention include regular physical activity, tobacco cessation, weight management, immunizations, and family planning to minimize risks associated with pregnancy. Prevention and evidence-based control of hypertension, diabetes, and dyslipidemia are essential. Occupational and environmental exposures, including poor indoor and outdoor air quality, should be addressed. Advances in pharmacotherapy for pulmonary arterial hypertension that target the endothelin, prostacyclin, and nitric oxide pathways and activin receptor inhibition have improved outcomes. Endothelin receptor antagonists, prostacyclin analogues, and phosphodiesterase 5 inhibitors are key treatment options. Combination therapy is recommended for patients with moderate to severe disease, whereas parenteral prostanoids are indicated for advanced pulmonary arterial hypertension. Right-sided heart failure, a major complication, is managed with fluid manage-ment and diuretics, with lung transplant evaluation and palliative shunt procedures considered for refractory cases. Addressing nutrition and iron deficiency are important supportive measures.

BMP9-mediated regulation of endothelin-1 requires integrated SMAD1/5 and SMAD2/3 signaling.

Jana Bagarova, Shreya Sangam, Luca Troncone +8 more

BMP9 is a pleiotropic growth factor cytokine with diverse roles in vascular development, homeostasis and disease. BMP9 regulates a broad array of vasoactive molecules that mediate endothelial and mural cell function, including ET-1, a potent vasoconstrictor, regulator of cell growth and fibrosis, and therapeutic target for pulmonary arterial hypertension (PAH). Consistent with its pleiotropic activities, BMP9 is unique in being able to recruit both BMP-responsive SMAD1/5/9 and TGFβ-responsive SMAD2/3 signaling effectors in endothelial cells, however, the physiologic significance of activating both pathways remains incompletely defined. We investigated the role of SMAD1/5/9 vs. SMAD2/3 signaling in BMP9-mediated regulation of ET-1, using primary and immortalized human and murine microvascular endothelial cells, with conditional knockout, small molecule inhibitor and siRNA strategies. BMP9-mediated expression of ET-1 requires coordinated activation of SMAD1/5/9 and SMAD2/3 effector pathways, both downstream of BMPR2, ALK1, and ENG. Analysis of the ET-1 promoter revealed that BMP9 requires, in addition to a SMAD3/4 binding site sufficient for TGFβ1-mediated transcription, a novel putative SMAD1/5 binding motif. BMP9-mediated regulation of endothelial ET-1 requires coordinated activation of both SMAD1/5 and SMAD2/3 downstream of ALK1, integrated at the promoter level, representing a non-canonical signaling motif linking BMP9 to a critical effector of vascular tone and remodeling in PAH and related vascular syndromes.

A Case of Atrial Septal Defect Unveiled by the Treatment for Pulmonary Arterial Hypertension.

Takaaki Fujii, Sayuri Yamabe, Yoshiro Tsuruta +10 more

We present a case of a 51-year-old woman with atrial septal defect (ASD) masked by pulmonary arterial hypertension (PAH). Three months after PAH treatment with a combination of endothelin receptor antagonist and phosphodiesterase five inhibitor, the transthoracic echocardiography revealed left-to-right shunting through a secundum ASD. The pulmonary vascular resistance decreased from 7.4 to 2.6 Wood units. Subsequent transcatheter closure of ASD using Occlutech Figulla Flex II device was successfully performed as a treat-and-repair strategy. Five months later, hemodynamics had normalized. Due to reduced shunt flow caused by PAH, ASD may not be detectable before treatment, so care must be taken not to overlook PAH associated with intracardiac defects.

Use of Sotatercept to Facilitate Transition From Intravenous to Oral Prostacyclin Therapy.

Chebly Dagher, Maria Akiki, Kristen Swanson +4 more

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular failure and high mortality. Parenteral prostacyclin therapy remains the cornerstone for high-risk patients but is limited by complications and reduced quality of life. Sotatercept, an activin signaling inhibitor, has recently emerged as an effective adjunct therapy in PAH, improving functional and hemodynamic outcomes. This case series evaluated whether the addition of sotatercept could facilitate the transition from intravenous (IV) to oral prostacyclin in eight high-risk PAH patients who had previously failed transition attempts. All patients received background dual therapy with endothelin receptor antagonists and phosphodiesterase-5 inhibitors and were transitioned from IV to oral treprostinil following the fifth dose of sotatercept. At 24 weeks, all eight patients successfully maintained oral therapy without re-initiation of IV prostacyclin. Significant improvements were observed in 6-min walk distance, WHO functional class, right ventricular systolic pressure, and PVR. No treatment discontinuations or serious adverse events occurred. These findings suggest that adjunctive sotatercept may enable safe and effective transition from parenteral to oral prostacyclin therapy, expanding treatment flexibility and improving quality of life in high-risk PAH patients. Prospective studies are warranted to confirm long-term outcomes.

Interleukin-35 alleviates pulmonary arterial hypertension by suppressing the VEGFA/VEGFR2 signaling pathway.

Jie Feng, Kai Li, Leilei Han +2 more

Pulmonary arterial hypertension (PAH) is a serious circulatory disorder defined by elevated pulmonary arterial pressure (PAP) with normal pulmonary capillary wedge pressure (PCWP), driven by pathological remodeling of pulmonary arterioles. If left untreated, it can lead to severe health complications and death. Current treatments, such as endothelin receptor antagonists and phosphodiesterase-5 inhibitors, prostacyclin analogs, and soluble guanylate cyclase stimulators-these agents relieve symptoms, improve exercise capacity, and delay disease progression but do not target the underlying vascular pathology. Because these therapies fail to improve long-term prognosis, they impose a heavy burden on patients, families, and society. Thus, there is an urgent need to develop new therapeutic agents that can treat PAH more effectively. Interleukin-35 (IL-35), which is primarily produced by regulatory T cells, is a potent molecule exhibiting significant anti-inflammatory and immunomodulatory properties. Recent research suggests that IL-35 shows promise as a novel therapeutic agent for PAH. However, the precise mechanism by which IL-35 influences pulmonary hypertension remains to be elucidated through further experimentation. To address this, we established animal and cellular models and analyzed molecular, functional, and structural changes using western blotting, PAP measurements, flow cytometry, EdU staining, scratch assay, blood biochemistry, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (H&E), Immunohistochemistry (IHC) and Masson's trichrome staining. Our results suggest that IL-35 alleviates PAH-induced inflammation, apoptosis, and smooth muscle cell proliferation, reduces PAP, and restores vascular remodeling, thereby mitigating both structural and functional damage in PAH.

A Systematic Literature Review Exploring the Efficacy and Safety of Tadalafil and Sildenafil in Pulmonary Arterial Hypertension.

Rajan Saggar, Nora Rahhali, Assunta Senatore +7 more

Pulmonary Arterial Hypertension (PAH) is a rare, chronic and progressive disease affecting the heart and lungs. Endothelin receptor antagonist (ERA) + phosphodiesterase type 5 inhibitor (PDE5i) treatment is recommended for all PAH patients. The two approved PDE5is are tadalafil and sildenafil. To determine the efficacy and safety outcomes for tadalafil and sildenafil as monotherapies or in combination with ERAs for treating PAH, from randomized controlled trials (RCTs) and real-world evidence studies (RWEs) identified by a systematic literature review (SLR). MEDLINE, Embase and Cochrane Libraries were searched in May 2024. Relevant outcomes included 6-min walk distance (6MWD), pulmonary vascular resistance (PVR) and safety. This report includes studies where patients were treated with either sildenafil or tadalafil. Fifteen RCTs and three RWEs investigated tadalafil (tadalafil 40 mg or 20 mg once daily) or sildenafil (20 mg three times a day). Mean 6MWD change from baseline (CFB) in patients receiving tadalafil or sildenafil monotherapy were comparable, however, in combination with an ERA, tadalafil may be more effective. Generally, there was more data for tadalafil + ERAs, showing marked improvement in mean PVR CFB, compared with patients receiving sildenafil. Conclusions on safety were limited. Risk of bias in RCTs was generally low but moderate in RWEs. Two studies reported patients who switched from sildenafil to tadalafil treatment, treatment transition was feasible. Although comparable when used as monotherapy, this qualitative analysis suggests that tadalafil + ERA combination therapy may have more favorable 6MWD improvements than sildenafil + ERA combination therapy.