Vascular Pharmacology[JOURNAL]
Sun
200 papers
Exercise pulmonary hypertension in chronic thromboembolic pulmonary disease without resting pulmonary hypertension: A systematic review and meta-analysis.
Biondi F, Ghelardoni S, Morrone D … +2 more , De Caterina R, Madonna R
Vascul Pharmacol · 2026 Mar · PMID 41570928 · Publisher ↗
Exercise pulmonary hypertension (exPH) is currently defined as a mean pulmonary artery pressure to cardiac output slope (mPAP/CO slope) greater than 3 mmHg/L/min during the transition from rest to end-exercise, and a nor...
Exercise pulmonary hypertension (exPH) is currently defined as a mean pulmonary artery pressure to cardiac output slope (mPAP/CO slope) greater than 3 mmHg/L/min during the transition from rest to end-exercise, and a normal mPAP at rest. ExPH may represent an early marker of vascular dysfunction in patients with chronic thromboembolic pulmonary disease (CTEPD) without resting pulmonary hypertension (pH). This is one of the possible complications of pulmonary embolism and is characterized by a variable degree of exercise intolerance. Its natural history is largely unknown and its clinical management is constrained by the lack of validated prognostic markers. We conducted a systematic review and meta-analysis to evaluate the prevalence of exPH and its prognostic role in CTEPD without resting PH. Secondary aims were to ascertain the prevalence of mPAP/CO and PAWP/CO slopes in CTEPD without resting pulmonary hypertension and in patients with post-capillary PH. Upon identification and screening, 12 studies satisfied the criteria for eligibility and were included in the systematic review, with a total of 373 patients. This data base consisted of studies with different designs. Quantitative data were meta-analyzed for each of the aims when provided by at least 5 studies. Approximately 50% of patients suffered from exPH, with a pooled prevalence of 0.50 as per random effect model and 0.44 as per fixed effect model with high heterogeneity. Mean mPAP/CO slope was 4.10 and 3.51 mmHg/L/min as per random effect meta-analysis or common effects model, respectively. The studies included did not provide evidence on the prognostic role in CTEPD without resting PH. Only a few data were reported on PAWP/CO slope and post capillary exPH. In conclusion, our systematic review indicates that ExPH is highly prevalent in CTEPD without resting PH, but its prognostic value is still to be defined.
Endothelial-to-mesenchymal transition primes vascular endothelial cells toward an osteochondrogenic fate.
Kishta F, Hall IF, Li G … +10 more , Tripathi T, Vermeren M, Cholewa-Waclaw J, Rossi F, Péault BM, Rodor J, Beqqali A, Sluimer JC, Crisan M, Baker AH
Vascul Pharmacol · 2026 Mar · PMID 41475635 · Publisher ↗
Endothelial-to-mesenchymal transition (EndMT), in which endothelial cells (ECs) lose their endothelial identity and acquire mesenchymal-like features, contributes to vascular dysfunction and remodeling in atherosclerosis...
Endothelial-to-mesenchymal transition (EndMT), in which endothelial cells (ECs) lose their endothelial identity and acquire mesenchymal-like features, contributes to vascular dysfunction and remodeling in atherosclerosis. However, the fate and function of these cells remain unclear. Here, we investigated their differentiation potential and functional properties to define how EndMT contributes to vascular dysfunction. Human umbilical vein ECs (HUVECs) were treated with transforming growth factor-β2 (TGF-β2) and interleukin-1β (IL-1β) for seven days to induce EndMT. Mesenchymal stem/stromal cell (MSC) identity was assessed by flow cytometry for canonical markers (CD44, CD73, CD105, CD90). Differentiation states were evaluated using published single-cell RNA sequencing (scRNA-seq) data of EndMT-treated HUVECs and validated under lineage-specific culture environments. In vivo analysis was performed using scRNA-seq data from EC lineage reporter mice in atherosclerosis models. EndMT-treated HUVECs displayed an intermediate mesenchymal phenotype, expressing CD44, CD73 and CD105 but lacking CD90, failing to meet MSC criteria. Potency analysis showed that 77 % of EndMT-treated HUVECs remained oligopotent, while 19 % acquired osteogenic and chondrogenic potential, accompanied by activation of lineage-associated transcriptional programs (RUNX2, BMPR1A, NOTCH2, WNT5A; CD151, ANXA6, DCN). In vivo, endothelial lineage-traced cells in atherosclerotic mice formed an EndMT cluster enriched for osteogenic and chondrogenic gene programs, including ossification and cartilage development pathways. We define a primed oligopotent state of EndMT-derived cells both in vitro and in vivo, marked by transition toward osteogenic and chondrogenic fates. These findings suggest that EndMT contributes to atherosclerosis by generating osteogenic- and chondrogenic-like cells, linking endothelial dysfunction to vascular calcification in disease.
Hemodynamic markers: CFD-based prediction of cerebral aneurysm rupture risk.
Bozorgpour R
Vascul Pharmacol · 2026 Mar · PMID 41455581 · Publisher ↗
Predicting which intracranial aneurysms will progress to rupture remains a major unmet need in neurosurgical practice. Conventional imaging provides limited insight into the hemodynamic forces acting on the aneurysm wall...
Predicting which intracranial aneurysms will progress to rupture remains a major unmet need in neurosurgical practice. Conventional imaging provides limited insight into the hemodynamic forces acting on the aneurysm wall, yet these forces play a central role in its long-term stability. To address this limitation, we developed a patient-specific computational pipeline capable of converting routine MRA data into detailed maps of aneurysmal blood-flow dynamics. The tool reconstructs vascular geometry directly from imaging and quantifies hemodynamic biomarkers associated with rupture risk, enabling clinicians to access physiologically meaningful information that is not visible on structural imaging alone. Using this framework, we analyzed six aneurysm cases with known longitudinal outcomes to determine whether baseline flow conditions differed between lesions that later ruptured and those that remained stable. High-resolution CFD simulations were used to compute wall shear stress (WSS), time-averaged WSS (TAWSS), oscillatory shear index (OSI), relative residence time (RRT), and endothelial cell activation potential (ECAP). Distinct hemodynamic patterns emerged: aneurysms that remained stable showed higher WSS/TAWSS and lower OSI/RRT, whereas aneurysms that ultimately ruptured exhibited low shear environments, stronger oscillatory flow, and greater endothelial activation. Regions with elevated OSI and RRT frequently coincide with vortex cores, suggesting localized flow disturbances that may serve as early indicators of wall vulnerability. These results demonstrate that clinically acquired MRA, when paired with a dedicated computational tool, can reveal baseline hemodynamic signatures predictive of future aneurysm behavior. This approach offers a noninvasive, imaging-driven method to support clinical decision-making, refine surveillance strategies, and improve individualized management of patients with intracranial aneurysms.
The pleiotropic effects of sotatercept.
Manzi G, Maggio E, Recchioni T … +8 more , Adamo FI, Caputo A, Mihai A, Papa S, Serino G, Scoccia G, Badagliacca R, Vizza CD
Vascul Pharmacol · 2026 Mar · PMID 41429404 · Publisher ↗
Recent randomized clinical trials (RCTs) have demonstrated the efficacy of sotatercept in the treatment of pulmonary arterial hypertension (PAH), leading to its approval by both the U.S. Food and Drug Administration (FDA...
Recent randomized clinical trials (RCTs) have demonstrated the efficacy of sotatercept in the treatment of pulmonary arterial hypertension (PAH), leading to its approval by both the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This novel first-in-class fusion protein acts as a ligand trap for select members of the transforming growth factor-beta (TGF-β) superfamily, thereby exerting a broad spectrum of biological effects. These include vascular remodeling (via Activin A and B inhibition), enhancement of angiogenesis (through modulation of BMP-9), stimulation of erythropoiesis (by targeting GDF-11), and, to a lesser extent, modulation of skeletal muscle homeostasis (through GDF-8/myostatin inhibition). This review focuses on the pleiotropic effects of sotatercept, with the aim of encouraging the reader to delve deeper into the drug's multifaceted mechanisms.
RNA-seq and ChIP-seq reveal microplastics induce endothelial-mesenchymal transition via HK2-mediated histone lactylation in pulmonary hypertension.
Long C, Lin M, Wang W … +3 more , Liu Y, Huang Z, Xu Z
Vascul Pharmacol · 2026 Mar · PMID 41352427 · Publisher ↗
Pulmonary hypertension (PH) is a life-threatening condition characterized by progressive pulmonary vascular remodeling, and endothelial-mesenchymal transition (EndMT) is recognized as a critical pathogenic process drivin...
Pulmonary hypertension (PH) is a life-threatening condition characterized by progressive pulmonary vascular remodeling, and endothelial-mesenchymal transition (EndMT) is recognized as a critical pathogenic process driving this remodeling. This study investigated the role of microplastics (MPs) in promoting EndMT in human pulmonary artery endothelial cells (HPAECs) and its underlying regulatory mechanism. We demonstrated that MPs were internalized by HPAECs, leading to significant downregulation of endothelial markers (CD31 and VE-cadherin) and upregulation of mesenchymal markers (α-SMA and vimentin), thereby promoting EndMT. In a rat model of PH induced by monocrotaline, intratracheal instillation of MPs further increased right ventricular and pulmonary arterial pressures, exacerbated vascular remodeling, and enhanced inflammatory infiltration. RNA-seq analysis revealed that MPs activated inflammatory pathways and enhanced glycolysis in HPAECs, with significant upregulation of glycolytic genes such as HK2. Knockdown of HK2 attenuated the cell viability and migratory ability of HPAECs and counteracted MP-induced EndMT. Additionally, MPs increased lactate production and histone lactylation, which were reversed by HK2 interference. ChIP-seq further confirmed the altered histone lactylation by MPs in HPAECs, including 603 genes with hyper-lactylation and 1292 genes with hypo-lactylation. Genes with hyper-lactylation were related to inflammation, and genes with hypo-lactylation were associated with epithelial/endothelial cell migration, angiogenesis, and vascular endothelial growth factor signaling pathway. Integrative analysis of the RNA-seq and ChIP-seq data identified four PH- and inflammation-associated differentially expressed genes exhibiting hyper-lactylation (FOXO3, RUNX1, TNFRSF11B, and SGK1). Among them, RT-PCR and ChIP-qPCR confirmed the upregulation and increased histone lactylation of TNFRSF11B and SGK1. These findings highlight the critical role of MPs in modulating metabolic and histone lactylation in PH and suggest potential therapeutic targets for mitigating PH progression.
Smooth muscle cell phenotypic modulation during atherosclerosis.
Frausto L, Scott ML, Orr AW … +1 more , Yurdagul A
Vascul Pharmacol · 2026 Mar · PMID 41349733 · Full text
Vascular smooth muscle cells (vSMCs) play a central role in atherosclerotic plaque development and stability through their remarkable phenotypic plasticity. In healthy vessels, contractile vSMCs maintain vascular tone an...
Vascular smooth muscle cells (vSMCs) play a central role in atherosclerotic plaque development and stability through their remarkable phenotypic plasticity. In healthy vessels, contractile vSMCs maintain vascular tone and structural integrity. During atherogenesis, lipid accumulation, inflammatory cues, growth factors, and mechanical stress drive vSMC dedifferentiation, proliferation, and migration into the intima. This transition involves downregulation of contractile genes regulated by SRF-myocardin and induction of synthetic, proliferative, inflammatory, macrophage-like, or osteogenic phenotypes, mediated in part by KLF4, PDGF, TNFα, oxidized lipids, and TGFβ signaling. Mechanotransduction through integrins and ECM remodeling reinforces these phenotypic shifts, with pathological stretch, matrix stiffening, and provisional matrix deposition promoting plasticity via RhoA/ROCK, FAK, and YAP/TAZ pathways. Clonal expansion of select medial vSMCs further shapes plaque architecture, while non-coding RNAs fine-tune phenotypic modulation at the post-transcriptional level. Collectively, these processes contribute to fibrous cap thinning, impaired efferocytosis, necrotic core expansion, and vascular calcification - features of vulnerable plaques. Here, we review the molecular, mechanical, and post-transcriptional mechanisms driving vSMC phenotypic modulation in atherosclerosis, highlighting their contributions to plaque progression and instability, and discussing emerging areas that may inform future therapeutic strategies.
Nebivolol in the therapeutic landscape of heart failure: Mechanisms and clinical outcomes.
Ginghina ER, Biondi-Zoccai G, Vitali A … +2 more , Di Napoli LF, Frati G
Vascul Pharmacol · 2026 Mar · PMID 41344604 · Publisher ↗
Heart failure (HF) remains a major global health challenge, marked by clinical heterogeneity and high morbidity, especially among elderly and comorbid patients. While β-blockers are central to HF management, conventional...
Heart failure (HF) remains a major global health challenge, marked by clinical heterogeneity and high morbidity, especially among elderly and comorbid patients. While β-blockers are central to HF management, conventional agents often present tolerability limitations, particularly in populations with preserved ejection fraction (HFpEF) or impaired vascular function. Nebivolol, a third-generation β-blocker characterized by high β₁-selectivity and nitric oxide-mediated vasodilation, offers a differentiated therapeutic profile with potential advantages in these subgroups. This review synthesizes current evidence on nebivolol's pharmacologic mechanisms, including its dual action on adrenergic and endothelial pathways, as well as its antioxidant and anti-inflammatory effects. Preclinical studies and translational biomarkers support their vascular and myocardial protective actions, while the SENIORS trial provides pivotal clinical evidence demonstrating efficacy across ejection fraction spectrums in elderly HF patients. Comparative data further reinforces its tolerability and favorable metabolic impact relative to traditional β-blockers. Nebivolol's role is also explored in guideline contexts and its potential utility in special populations such as those with renal impairment, diabetes, or cancer therapy-related cardiac dysfunction. Looking ahead, advances in pharmacogenomics, digital phenotyping, and adaptive trial designs may help personalize nebivolol therapy. This review underscores nebivolol's emerging position in the evolving landscape of HF treatment.
Amylin receptors as therapeutic targets in obesity: Emerging peptide-based strategies.
Rejili M, Hussain MS, Khan Y … +5 more , Haouala F, Ganesan S, Sahoo S, Pal A, Arora V
Vascul Pharmacol · 2026 Mar · PMID 41344603 · Publisher ↗
Obesity is a chronic, relapsing metabolic disorder driven by complex genetic and environmental factors, leading to an imbalance in energy regulation. Despite the presence of GLP-1 receptor agonists with induced mild weig...
Obesity is a chronic, relapsing metabolic disorder driven by complex genetic and environmental factors, leading to an imbalance in energy regulation. Despite the presence of GLP-1 receptor agonists with induced mild weight loss, there are significant unmet clinical needs with poor efficacy and tolerability problems. Amylin, a neuroendocrine hormone co-released with insulin, controls hunger, gastric motility, glucagon secretion, and energy metabolism via divergent amylin receptor (AMYR) subtypes (1-3), namely the calcitonin receptor (CTR) and the receptor activity-modifying proteins (RAMPs). Novel insight into the molecular make-up of AMYRs and central signaling reinforces its key function in modulating homeostatic and hedonic feeding mechanisms. The article is a review of the emerging preclinical and clinical data regarding the application of peptide-based amylin receptor agonists (AMYRAs), including pramlintide and cagrilintide, KBP-series DACRAs, and investigational drugs, including ZP8396 and amycretin. The agents show enhanced pharmacokinetics, synergy with GLP-1 receptor agonist, and favorable impact on weight regulation and metabolic plasticity. Genetic CALCR and RAMP mutations, new delivery approaches, and dual therapy by digital health technologies and bariatric surgery are also discussed in this review. Of particular interest, amylin-derived medications can have advantages over weight loss but definite disease-modifying action remains to be determined. Taken together, AMYRAs represent a potential category of therapeutics with promising disease-modifying effects that goes beyond weight loss, providing fresh perspectives for precision obesity management by 2030.
ASPYRE-1 study: An Italian multicenter prospective study on pulmonary hypertension modality of death and validation of REVEAL risk score.
Papa S, D'Alto M, Scelsi L … +51 more , Acquaro M, Adamo F, Albera C, Ameri P, Argiento P, Badagliacca R, Carignola R, Casu G, Confalonieri M, Corda M, Correale M, Cresci C, D'Alessandro F, D'Agostino C, De Caterina R, De Michele L, De Tommasi E, Di Marino S, Filomena D, Galgano G, Garascia A, Giannazzo D, Greco A, Grimaldi M, Lanzarone N, Lattanzio M, Lombardi CM, Madonna R, Maggio E, Manzi G, Mercurio V, Mihai A, Mulè M, Orlando A, Paciocco G, Pezzuto B, Piccinino C, Poscia R, Raineri C, Recchioni T, Romaniello A, Romeo E, Serino G, Serra W, Stolfo D, Tricarico L, Vatrano M, Vitulo P, Vizza CD, Ghio S, Italian Pulmonary Hypertension NETwork (iPHNET)
Vascul Pharmacol · 2026 Mar · PMID 41325956 · Publisher ↗
BACKGROUND: Our understanding of pulmonary arterial hypertension (PAH) pathophysiology and treatment has significantly improved over time. Within this scenario we established the Italian Network on Pulmonary Arterial Hyp...
BACKGROUND: Our understanding of pulmonary arterial hypertension (PAH) pathophysiology and treatment has significantly improved over time. Within this scenario we established the Italian Network on Pulmonary Arterial Hypertension (IPHNET), promoting a national prospective registry (ASPYRE-1) to collect data on contemporary PAH patients and to define the baseline features of Italian PAH patients. The aim of our study is to show the clinical characteristics of the Italian PAH patients. This cohort of patients will be followed in the ongoing registry to provide important insight into risk stratification and mode of death. METHODS: Twenty-six PAH centers were initially involved in the registry. Data were collected on anthropometric measurements, medical history, vital signs, clinical signs of heart failure, physical examination, laboratory tests (hematology and clinical chemistry), WHO functional class evaluation, non-encouraged 6-min walk test (6MWT), echocardiographic imaging and right heart catheterization (RHC) of outpatients and inpatients with PAH (Group 1) diagnosis. All the centers shared a common database for the prospective follow-up of the patients. RESULTS: between May 2014 and January 2023, a total of 500 prevalent patients with clinical diagnosis of PAH were enrolled: idiopathic (40.6 %), heritable (4.6 %), associated with drug or toxins (0.8 %), associated with connective tissue disease (26.4 %), associated with HIV infection (4.8 %), associated with portal hypertension (3.8 %), associated with congenital heart disease (16,4 %), with features of venous/capillary involvement (1.4 %), others (1.2 %) were enrolled. According to the ERS/ESC guidelines risk assessment, 207 (41.4 %) patients were at low risk, and 286 (57.2 %) were at intermediate risk. According to the REVEAL 2.0 score, 352 (70.4 %) patients were at low risk (score < 7), 93 (18.6 %) were at intermediate risk (score 7-8), and 55 (11 %) were at high risk (score > 8), Of the total patient population, 177 (35.4 %) received monotherapy, 222 (44.4 %) received double combination therapy, and 101 (20.2 %) received triple combination therapy. CONCLUSION: Built as a collaborative registry of centers treating PAH patients in Italy, it holds significant promise for addressing several critical needs within the field, including patients' clinical trajectory and risk stratification.
Corrigendum to "Lack of AMP-activated protein kinase-α1 reduces nitric oxide synthesis in thoracic aorta perivascular adipose tissue" [Vascular Pharmacology 157 (2024)107437].
Hwej A, Al-Ferjani A, Alshuweishi Y … +3 more , Naji A, Kennedy S, Salt I
Vascul Pharmacol · 2025 Dec · PMID 41241650 · Publisher ↗
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Endothelial and non-endothelial actions of estrogen receptor subtypes in male and female mouse Aorta.
Elsaid B, Kopaliani I, Zatschler B … +3 more , Seif A, Speier S, Deussen A
Vascul Pharmacol · 2025 Dec · PMID 41213389 · Publisher ↗
Estrogen's role in cardiovascular health remains inconsistent. This study investigates the non-genomic vasorelaxant effects of 17β-estradiol, focusing on sex-specific differences in estrogen receptor (ER) subtypes (ERα,...
Estrogen's role in cardiovascular health remains inconsistent. This study investigates the non-genomic vasorelaxant effects of 17β-estradiol, focusing on sex-specific differences in estrogen receptor (ER) subtypes (ERα, ERβ and GPER), endothelial function, and phosphoinositide 3-kinase (PI3K) pathway. Ex vivo experiments using thoracic aorta from male and female wild-type mice assessed ER expression by immunofluorescence and vascular reactivity by wire myography. Vasorelaxant responses to 17β-estradiol and ER-selective agonists (PPT, DPN and G1) were examined. Some experiments were conducted in the presence of pharmacological inhibitors targeting endothelium-dependent relaxation pathways (L-NMMA, indomethacin and apamin/charybdotoxin), as well as PI3K inhibitor LY294002. In vitro, primary mouse aortic smooth muscle cells (MASMCs) were used to assess acute effects of 17β-estradiol on myosin light chain (MLC) and Akt phosphorylation via western blot. ER subtypes were observed in the endothelial and medial regions of the vessel wall. 17β-estradiol induced similar vasorelaxation in both sexes, with subtle differences in endothelial ERβ and GPER. Nitric oxide synthase (NOS) inhibition attenuated vasorelaxation, with modest sex-specific differences in ERβ. PI3K inhibition augmented vasorelaxation regardless of endothelial integrity, exhibiting slight sex variability across ER subtypes. MASMCs showed a near-significant increase in MLC phosphorylation with 17β-estradiol, without significant Akt activation. In conclusion, estrogen induces NOS dependent vasorelaxation in mouse aorta, with no sex differences. However, subtle sex differences among ER subtypes were observed in the contribution of endothelium, NOS and PI3K pathways. The PI3K pathway may attenuate vasorelaxation by promoting MLC phosphorylation in vascular smooth muscle, and its inhibition unmasks the vasorelaxant potential of 17β-estradiol.
Emerging role of the adaptive immunity in aortic aneurysm and dissection.
Hu YN, Wang M, Zhang Z
Vascul Pharmacol · 2025 Dec · PMID 41207455 · Publisher ↗
Aortic aneurysm and dissection (AAD) is a critical aortic disease with high mortality. AAD is characterized by aortic inflammation, which manifests as the infiltration of immune cells and the accumulation of inflammatory...
Aortic aneurysm and dissection (AAD) is a critical aortic disease with high mortality. AAD is characterized by aortic inflammation, which manifests as the infiltration of immune cells and the accumulation of inflammatory mediators. Studies have predominantly focused on the innate immune response, while the role of adaptive immunity in AAD remains poorly characterized. Given the substantial knowledge gaps, this review systematically outlines the development of the adaptive immune response in AAD - from antigen initiation and lymphocyte activation to its ultimate effects on the aortic wall. Additionally, promising immunomodulatory therapies, such as biologic agents and cell-based treatments, are discussed. This review underscores the need for a deeper understanding of the contributions of adaptive immunity to AAD, as elucidating these mechanisms could inform precise therapeutic strategies for this serious condition.
Elastase-2 deletion prevents vascular remodeling and abdominal aortic aneurysm development in a mice model induced by angiotensin II.
Mestriner F, Dugaich VF, Dantas PB … +11 more , Kovacs HZ, Blascke de Mello MM, Pedersoli CA, da Costa RM, Jordani MC, Ramalho LNZ, de Castro MM, Silva-Neto JA, Tostes Passaglia RCA, Ribeiro MS, Becari C
Vascul Pharmacol · 2025 Dec · PMID 41187820 · Publisher ↗
Abdominal aortic aneurysm (AAA) involves the remodeling of the aortic wall extracellular matrix (ECM), compromising biomechanical support and increasing the risk of aortic dissection and rupture. Activation of the renin-...
Abdominal aortic aneurysm (AAA) involves the remodeling of the aortic wall extracellular matrix (ECM), compromising biomechanical support and increasing the risk of aortic dissection and rupture. Activation of the renin-angiotensin system (RAS), particularly the synthesis of angiotensin II (Ang II), plays a fundamental role in AAA initiation and progression. Elastase-2 (ELA-2), a chymotrypsin-like serine protease, contributes to tissue Ang II generation and may be a key player in AAA pathophysiology. This study investigated the effects of ELA-2 deletion in a murine model of angiotensin II-induced AAA, with particular focus on determining whether ELA-2 modulates vascular contractility and aortic relaxation in wild-type mice and whether these effects are absent in ELA-2 knockout mice. We additionally examined the cellular alterations within the aortic wall that contribute to increased reactive oxygen species generation during AAA development. Male C57BL/6 J (wild-type, WT) and ELA-2 knockout (ELA-2KO) mice, aged 10 to 15 weeks, were infused with Ang II (1500 ng/kg/min) for 28 days to induce AAA formation. Wild-type (WT) mice developed AAA, as evidenced by aortic dilation, structural remodeling, fibrosis, and inflammation. In contrast, ELA-2KO mice showed markedly reduced pathological changes following Ang II-induced AAA. Histological and biochemical analyses of the abdominal aorta revealed enhanced gelatinolytic activity, macrophage infiltration, and oxidative stress in WT mice, all of which were significantly attenuated in ELA-2KO mice. Furthermore, transcriptional profiling demonstrated that ELA-2 deletion maintained a contractile VSMC phenotype, suggesting a protective effect against maladaptive vascular remodeling. In summary, ELA-2 deficiency prevented Ang II- induced AAA formation and pathological vascular remodeling, highlighting its potential as a therapeutic target to mitigate AAA progression.
Growth differentiation factor 15 protects against diabetic endothelial dysfunction by AMP-activated protein kinase mediation.
Zhao W, Liu Y, Cui Z … +4 more , Li X, Guo H, Chen X, Zhang H
Vascul Pharmacol · 2025 Dec · PMID 41130428 · Publisher ↗
AIMS: Endothelial dysfunction is a hallmark of diabetes-associated cardiovascular complications, yet its molecular mechanisms remain incompletely elucidated. Growth differentiation factor 15 (GDF15) has emerged as an imp...
AIMS: Endothelial dysfunction is a hallmark of diabetes-associated cardiovascular complications, yet its molecular mechanisms remain incompletely elucidated. Growth differentiation factor 15 (GDF15) has emerged as an important modulator in metabolic and cardiovascular diseases; however, its role in diabetic endothelial dysfunction is poorly understood. This study aims to investigate the therapeutic potential of GDF15 in diabetic endothelial dysfunction and to elucidate the underlying mechanisms. METHODS: db/db mouse aortas or high glucose/high lipid (HG/HL)-treated C57BL/6 mouse aortas were exposed to GDF15 for acute or prolonged durations. Endothelium-dependent relaxation (EDR) was evaluated using wire myography. Meanwhile, western blotting was performed to assess protein levels of nuclear factor erythroid 2-related factor 2 (NRF2), NADPH oxidase 2 (NOX2), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), total AMP-activated protein kinase (AMPK), and phosphorylated AMPK in endothelial cells treated with GDF15 in the presence or absence of HG/HL. Reactive oxygen species (ROS) production in en face endothelial cells of mouse aortas was measured via confocal microscopy. RESULTS: Exogenous GDF15 acute or prolonged administration markedly ameliorated HG/HL- and diabetes-induced endothelial dysfunction and excess reactive oxygen species (ROS) generation. Meanwhile, GDF15 counteracted HG/HL-induced changes in NOX2, NRF2, ACE, and ACE2 protein expression in endothelial cells. These beneficial effects of GDF15 were mechanistically linked to AMPK upregulation, as evidenced by elevated AMPK levels in GDF15-treated endothelial cells, and the suppression of GDF15's vasoprotective effects by the AMPK inhibitor Compound C. CONCLUSIONS: Our findings demonstrate that GDF15 ameliorates diabetic endothelial dysfunction and oxidative stress by AMPK-dependent pathways in endothelial cells. These results highlight GDF15 as a promising therapeutic target for mitigating oxidative stress and preserving diabetic endothelial dysfunction.
Pre-eclampsia with inflammatory and pro-resolving mediator fluctuations - contributions from hemolytic protozoan parasites.
Roe K
Vascul Pharmacol · 2025 Dec · PMID 41101716 · Publisher ↗
Pre-eclampsia (PE) and eclampsia are inflammatory hypertension diseases which have globally caused countless millions of fatalities among pregnant women, and their pathogenesis has been a centuries-long mystery. Substant...
Pre-eclampsia (PE) and eclampsia are inflammatory hypertension diseases which have globally caused countless millions of fatalities among pregnant women, and their pathogenesis has been a centuries-long mystery. Substantial experimental evidence, including extensive cytokine signatures, symptoms, characteristics and drug interactions, suggest initiation by hemolytic protozoan parasite infections which provide heme and iron for reactivation of iron-deprived bacterial and/or viral infections. However, there are unexplained PE and eclampsia secondary characteristics: (1) Why are endothelial dysfunction and vascular inflammation ubiquitous in pregnancies complicated by PE and eclampsia? (2) Why does pregnancy termination resolve the inflammation of pregnancies complicated by PE and eclampsia? (3) Why do omega-3 polyunsaturated fatty acids, including DHA and EFA and their derived resolvins, have decreased blood levels, whereas omega-6 polyunsaturated fatty acids have elevated levels? (4) Why is low-dose aspirin therapy frequently effective in preventing PE and eclampsia? There are now plausible explanations for these secondary characteristics. These explanations also support the hypothesis that PE and eclampsia are diseases induced by bacterial or viral infections concurrent with an almost asymptomatic strain of hemolytic protozoan parasite infection providing a virulence boost, with the reactivated infections inducing chronic inflammation. This also causes abnormal fluctuations in special pro-resolving mediators, including lipoxins, resolvins, protectins and maresins, which would normally participate in resolving acute inflammations.
Hypothalamic regulation of obesity: Revealing the therapeutic potential of a novel anti-obesity peptide.
Choo YN, Narayanan R, Subramaniyan V
Vascul Pharmacol · 2025 Dec · PMID 41093047 · Publisher ↗
Obesity is a chronic, complex condition defined by excessive fat buildup due to an imbalance between caloric consumption and energy expenditure. The significant global rise in prevalence of obesity is associated with num...
Obesity is a chronic, complex condition defined by excessive fat buildup due to an imbalance between caloric consumption and energy expenditure. The significant global rise in prevalence of obesity is associated with numerous comorbidities, such as cardiovascular disease, type 2 diabetes, and non-alcoholic fatty liver disease. Conventional management approaches, including diet, exercise, pharmacotherapy, and bariatric surgery, may demonstrate restricted long-term effectiveness owing to inadequate adherence and physiological adjustments. Recent advancements in neuroscience underscore the hypothalamus as a pivotal regulator of energy balance via essential nuclei, including the arcuate nucleus (ARC), paraventricular nucleus (PVN), lateral hypothalamic area (LHA), and ventromedial nucleus (VMN). This review examines the therapeutic potential of a new anti-obesity peptide that targets hypothalamic signalling pathways. Preclinical and clinical evidence endorses the utilization of glucagon-like peptide-1 receptor (GLP-1R) agonists and novel multi-receptor drugs such as AMG 133, which integrate GLP-1R activation with glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonism. These therapies exhibit improved weight reduction and metabolic enhancement. Moreover, the integration of hypothalamic peptide therapy with lifestyle modifications or post-bariatric care provides synergistic advantages. Notwithstanding favorable results, peptide therapy encounters obstacles such as administration methods, sustained effectiveness, and expense. Overcoming these obstacles is crucial for the effective implementation of peptide-based treatments in sustained clinical obesity control.
The endothelium at the crossroads of multi-organ pathology: Insights from organ-on-chip models.
Ghosh S, Shukla PC, Das S
Vascul Pharmacol · 2025 Dec · PMID 41076171 · Publisher ↗
Endothelial barrier function is indispensable in maintaining vascular-tissue-organ homeostasis. Altered release of vasoactive substances along with fluctuating shear stress patterns result in an impaired barrier function...
Endothelial barrier function is indispensable in maintaining vascular-tissue-organ homeostasis. Altered release of vasoactive substances along with fluctuating shear stress patterns result in an impaired barrier function leading to transmigration of blood components, tumor infiltrates and pathogens. Organ-on-chip (OoC) technology leverage microfabrication techniques to develop dynamic, three-dimensional (3D) in vitro platforms that closely mimic the structural and functional characteristics of human tissues, including the vasculature. These systems offer powerful tools for modeling disease mechanisms with high physiological relevance and are increasingly utilized in drug development, diagnostics, and therapeutic screening. By integrating biomimetic vascular environments, OoC platforms allow for the investigation of how endothelial barrier disruption, inflammatory signaling, and mechanical cues contribute to pathophysiology. Importantly, since endothelial dysfunction often precedes clinical symptoms, these models offer promising avenues for early disease detection and intervention. Together, these approaches provide a roadmap for using organ-on-chip systems to dissect vascular contributions to disease and to improve predictive, human-relevant preclinical models.
Efficacy and safety of lorundrostat in patients with uncontrolled or resistant hypertension: A systematic review and meta-analysis with trial sequential analysis.
Shalabi L, Tawfik AM, Al Zoubi BM … +3 more , Al Othman A, Zreigh S, Abuelazm M
Vascul Pharmacol · 2025 Dec · PMID 41067555 · Publisher ↗
BACKGROUND: Uncontrolled hypertension (HTN) remains a challenge despite multiple anti-hypertensive medications. This study systematically evaluates the efficacy and safety of Lorundrostat, a novel aldosterone synthase in...
BACKGROUND: Uncontrolled hypertension (HTN) remains a challenge despite multiple anti-hypertensive medications. This study systematically evaluates the efficacy and safety of Lorundrostat, a novel aldosterone synthase inhibitor, in patients with uncontrolled hypertension. METHODS: A comprehensive search of major electronic databases was conducted until Jul 14, 2025, to identify randomized controlled trials (RCTs) comparing Lorundrostat with placebo. The primary outcomes included changes in office systolic and diastolic blood pressure (BP). A random-effects model was used to pool the data, presented as risk ratios (RR) or mean differences (MD) with 95 % confidence intervals (CIs). RESULTS: The pooled analysis of three RCTs comprising 1562 patients demonstrated that lorundrostat yielded statistically significant reductions in both office systolic BP (MD = -8.26 mmHg; 95 % CI: -10.87 to -5.64; p < 0.0001) and diastolic BP (MD = -3.53 mmHg; 95 % CI: -5.62 to -1.43; p = 0.001). However, Lorundrostat was associated with increased risks of hyperkalemia (RR = 7.93; 95 % CI: 1.55 to 40.64; p = 0.0131), hyponatremia (RR = 1.96; 95 % CI: 1.15 to 3.35; p = 0.0133), hypotension (RR = 3.06; 95 % CI: 1.15 to 8.11; p = 0.0250), and any adverse events (RR = 1.47; 95 % CI: 1.29 to 1.67; p < 0.0001). CONCLUSION: Lorundrostat effectively controls blood pressure in patients with uncontrolled hypertension; however, it also increases the incidence of adverse events, and further large-scale trials are needed to confirm long-term efficacy and safety. PROSPERO ID: CRD420251107424.
Transcellular permeability of arterial endothelium to plasma LDL, an underexplored target in treating atherosclerosis: Novel insights and potential treatment strategies.
Bolanle IO, de Liedekerke Beaufort G
Vascul Pharmacol · 2025 Dec · PMID 41046111 · Publisher ↗
Ischaemic heart disease, of which atherosclerosis is the primary substrate, continues to be a leading cause of death globally. Atherosclerosis is characterised by the accumulation of cholesterol, mainly from circulating...
Ischaemic heart disease, of which atherosclerosis is the primary substrate, continues to be a leading cause of death globally. Atherosclerosis is characterised by the accumulation of cholesterol, mainly from circulating low-density lipoprotein (LDL), within the arterial wall. LDL influx is determined by the product of two variables: the concentration of LDL in plasma and the permeability of the endothelium to LDL. Lowering the former is the primary therapeutic strategy employed today. Meanwhile, lowering permeability ought to be equally beneficial, and its effect on influx would likely be multiplicative with lipid lowering, but it is currently underexplored as a target in treating atherosclerosis. Advances in electron microscopy have helped improve our understanding of the three primary routes through which LDL permeates the endothelium: transcellular (via passive and active, receptor-mediated transport that involves the movement of LDL as cargo inside caveolae), paracellular (via interendothelial/paracellular junctions), and through cells undergoing mitosis and apoptosis (leaky junctions). We have therefore highlighted in this review, based on recent advances in experimental and translational investigations viable pharmacological agents that modulate transendothelial permeability to LDL as potential treatment options for atherosclerosis.
Apelin in glioblastoma: A dual target for tumor and vascular intervention.
Wachholz GE, van Loon K, Griffioen AW
Vascul Pharmacol · 2025 Dec · PMID 41038495 · Publisher ↗
Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor in adults, marked by rapid progression, profound intratumoral heterogeneity and poor prognosis despite multimodal therapy. Current standard-of-care...
Glioblastoma (GBM) is the most prevalent and lethal primary brain tumor in adults, marked by rapid progression, profound intratumoral heterogeneity and poor prognosis despite multimodal therapy. Current standard-of-care treatments, including maximal surgical resection followed by radiotherapy and temozolomide chemotherapy, offer only modest survival benefits, with most patients facing inevitable recurrence. A defining feature of GBM is its pronounced vascular proliferation, which supports tumor progression. This has spurred interest in targeting angiogenesis as a potential treatment approach. Apelin, a peptide involved in the regulation of angiogenesis and endothelial cell proliferation, has emerged as a key player in GBM pathogenesis. The Apelin/APJ signaling pathway is implicated in promoting tumor vascularization, invasiveness, and resistance to therapy, making it a promising therapeutic target. This review explores the role of Apelin/APJ pathway in GBM progression, focusing on its contribution to angiogenesis, as well as tumor growth and invasiveness. By integrating current findings, we aim to establish the rationale for targeting Apelin signaling as a novel therapeutic strategy in GBM, with the ultimate goal of overcoming treatment resistance and improving patient outcomes.
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