Vascular Pharmacology[JOURNAL]
Sun
200 papers
Interplay between Na/K-ATPase-dependent Src-mediated Ca sensitization and BK channel negative feedback regulates rat mesenteric artery contraction.
Nielsen DL, Khalid JA, Martínez AG … +5 more , Melnikova EV, Risager BH, Schubert R, Staehr C, Matchkov VV
Vascul Pharmacol · 2026 Jul · PMID 42398874 · Publisher ↗
The Na/K-ATPase α isoform regulates vascular tone by modulating Na/Ca exchange and Src kinase-dependent signaling within membrane microdomains. Inhibition of the Na/K-ATPase by cardiotonic steroids promotes vascular cont...
The Na/K-ATPase α isoform regulates vascular tone by modulating Na/Ca exchange and Src kinase-dependent signaling within membrane microdomains. Inhibition of the Na/K-ATPase by cardiotonic steroids promotes vascular contraction through increased intracellular Ca and enhanced Ca sensitization of the contractile apparatus. This effect is counterbalanced by a negative feedback mechanism involving large-conductance Ca-activated K (BK) channels. Given inconsistent reports regarding ouabain-induced potentiation of agonist-evoked vasoconstriction, we hypothesized that the effects of ouabain depend on the agonist (thromboxane A₂ receptor agonist U46619, noradrenaline, and the α-adrenoceptor agonist methoxamine) used. We specifically assessed changes in intracellular Ca, Ca sensitization, and the contribution of BK-channel-mediated feedback. Rat mesenteric small arteries were studied using isometric myography. Intracellular Ca was measured with the ratiometric dye FURA-2/AM, and signaling pathways were analyzed by Western blotting. Micromolar ouabain enhanced U46619-induced contraction but had no statistically significant effect on responses to noradrenaline or methoxamine. BK channel inhibition with iberiotoxin increased sensitivity to U46619 via elevated intracellular Ca. Combined ouabain and iberiotoxin treatment increased basal tone and augmented contractile responses to all agonists tested. Notably, ouabain enhanced Ca sensitization during U46619 stimulation through Src-dependent MYPT1 phosphorylation. Ouabain also increased Src and MYPT1 phosphorylation during both U46619 and methoxamine stimulation. These findings identify the Na/K-ATPase as a signaling scaffold that promotes Src-mediated Ca sensitization. This pro-contractile effect requires a sufficient intracellular Ca level, partly regulated by BK-channel dependent negative feedback.
Generation and validation of a Myh11Dre-Spp1Cre intersectional mouse model for lineage tracing of disease-associated smooth muscle cell states.
Tu Y, Ishimwe N, Ofori B … +3 more , Aherrahrou R, Dong K, Long X
Vascul Pharmacol · 2026 Jul · PMID 42386018 · Publisher ↗
BACKGROUND: Phenotypic modulation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular remodeling and cardiovascular disease. Recent lineage-tracing and single-cell transcriptomic studies have identified sec...
BACKGROUND: Phenotypic modulation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular remodeling and cardiovascular disease. Recent lineage-tracing and single-cell transcriptomic studies have identified secreted phosphoprotein 1 (SPP1) as a prominent marker associated with disease-associated VSMC states, particularly those linked to fibrotic remodeling and vascular calcification. However, the cellular origins and fate of SPP1-associated VSMC populations remain incompletely understood. METHODS AND RESULTS: We generated a novel Spp1-rSTOPr-Cre (Spp1Cre) knock-in mouse line in which Cre recombinase is expressed from the endogenous Spp1 locus following Dre-mediated excision of a rox-flanked transcriptional STOP cassette. Correct targeting of the knock-in allele was validated by internal, 5' junction, 3' junction, and long-range PCR analyses, as well as Sanger sequencing. To establish an intersectional lineage-tracing strategy, Spp1Cre mice were crossed with Myh11DreER and Rosa26-RSR-LSL-tdTomato-LSL-eGFP reporter mice, enabling permanent labeling of VSMC-derived populations following activation of the endogenous Spp1 locus. Under physiological conditions, GFP-positive cells were detected at low frequency within the vascular wall and were predominantly negative for the contractile markers ACTA2 and MYH11. As a proof-of-principle application, GFP-positive cells markedly expanded within atherosclerotic lesions induced by PCSK9-AAV and high-fat diet feeding. These lineage-traced cells remained largely ACTA2- and MYH11-negative, consistent with a modulated phenotype. Notably, only a minority of GFP-positive cells expressed SPP1 or fibronectin at the time of analysis, demonstrating the utility of permanent lineage tracing for tracking cells with a history of endogenous Spp1 activation during vascular remodeling. CONCLUSION: We report the generation and validation of a novel Myh11Dre-Spp1Cre intersectional mouse model for lineage tracing of VSMC-derived populations that have activated the endogenous Spp1 locus. This genetic resource provides a valuable platform for investigating the origin, fate, and phenotypic evolution of Spp1-associated VSMC populations during vascular remodeling and cardiovascular disease.
Prediction of peri-procedural cerebrovascular accidents in patients with severe peripheral artery disease undergoing transcatheter aortic valve replacement.
Costa G, Mazzola M, Sticchi A … +55 more , Palmerini T, Saia F, Bruno AG, Kim WK, Renker M, Iadanza A, Fineschi M, Vanhaverbeke M, De Backer O, Romagnoli E, Burzotta F, Trani C, Adrichem R, Van Mieghem NM, Tomii D, Pilgrim T, Aranzulla TC, Musumeci G, Adam M, Meertens MM, Hector Alfonso Alvarez Covarrubias, Joner M, Meucci F, Di Mario C, Loretz L, Toggweiler S, Testa L, Bedogni F, Berti S, Ancona MB, Montorfano M, Gmeiner J, Braun D, Nerla R, Castriota F, Barbanti M, Tamburino C, Leone PP, Reimers B, Stefanini G, Sudo M, Nickenig G, Piva T, Scotti A, Latib A, Vercellino M, Porto I, Frumento P, Codner P, Kornowski R, Bartorelli AL, Tarantini G, Fraccaro C, Abdel-Wahab M, De Carlo M
Vascul Pharmacol · 2026 Jun · PMID 42372999 · Publisher ↗
OBJECTIVES: Several models have been evaluated for the prediction of transcatheter aortic valve replacement (TAVR)-related cerebrovascular accidents (CVA). The HOSTILE registry recently investigated TAVR outcomes in pati...
OBJECTIVES: Several models have been evaluated for the prediction of transcatheter aortic valve replacement (TAVR)-related cerebrovascular accidents (CVA). The HOSTILE registry recently investigated TAVR outcomes in patients with severe peripheral artery disease (PAD), assessed using a multi-parameter score (HOSTILE score). Among patients treated with transfemoral access (TFA), higher HOSTILE score was associated with higher rates of CVA. We sought to assess the efficacy of different modalities of risk estimation for TAVR-related CVA prediction in a population with severe PAD. METHODS: The predictive ability of the risk assessment modalities was compared using the area under the receiving-operator characteristic (ROC) curve and Harrell's C-statistic. The pre-defined outcome was any CVA occurring within 30 days after TAVR. RESULTS: The study population consisted of 1707 patients, 518 (30.3%) treated via TFA and 1189 treated via transthoracic and trans-axillary routes. The CHADS-VASc and the HOSTILE score showed fair performance only in the TFA cohort (AUC 0.68, 95% CI 0.53-0.83, and 0.68, 95% CI 0.55-0.81, respectively); values of CHADS-VASc >5 and HOSTILE >6 exhibited the best discriminatory ability. The highest risk group (CHADS-VASc >5 and HOSTILE >6) showed a five-fold higher incidence of CVA as compared to the other groups (incidence 6.7%; HR: 5.38, CI95%: 1.80-16.01; p = 0.003). CONCLUSIONS: In a population of patients with severe PAD treated with TAVR via TFA, the integration of a clinical score (CHADS-VASc score) with a purely anatomical one (HOSTILE score) increased the discriminative ability towards 30-day CVA. Further analyses are needed in order to prospectively evaluate this strategy in different cohorts.
Vascularized tumor organoids as models for interpreting therapeutic response.
Huang S, Han S, Wang K
Vascul Pharmacol · 2026 Jun · PMID 42323958 · Publisher ↗
Vascularized tumor organoids are increasingly used to model therapeutic response, yet their value depends not simply on vascular complexity, but on whether vascularization improves response attribution. This review exami...
Vascularized tumor organoids are increasingly used to model therapeutic response, yet their value depends not simply on vascular complexity, but on whether vascularization improves response attribution. This review examines two linked determinants of pharmacological interpretability, the endothelial interface and the transport barrier, and uses them to classify vascularized tumor organoid models by functional consequence. Across model classes, vascularization can reshape tumor state, define drug entry, constrain tissue penetration, and impose cargo- and cell-dependent access. Therapeutic response in these systems should therefore be interpreted not as a direct measure of intrinsic sensitivity, but as a composite readout shaped by exposure, penetration, and endothelial-state modulation.
Spermidine ameliorates BK channel dysfunction in diabetic coronary smooth muscle cells via PKM2/STAT3/FBXO32 axis.
Zhang ZY, Zhou JB, Yang YJ … +10 more , Zhao SY, Fan SY, Pan L, Shen JX, Wang C, Shao YG, Zheng J, Qian LL, Dang S, Wang RX
Vascul Pharmacol · 2026 Jun · PMID 42303097 · Publisher ↗
BACKGROUND: Spermidine (SPD) exhibits potential protective effects against diabetic-induced BK channel dysfunction, though the molecular mechanisms remain unclear. This study investigated SPD-mediated regulation of large...
BACKGROUND: Spermidine (SPD) exhibits potential protective effects against diabetic-induced BK channel dysfunction, though the molecular mechanisms remain unclear. This study investigated SPD-mediated regulation of large-conductance calcium- and voltage-activated potassium channel (BK channel) function in coronary smooth muscle cells (SMCs) and the underlying molecular pathways. METHODS: Rats were randomly divided into: control (Ctrl), diabetes mellitus (DM), and DM with SPD treatment (DM + SPD) groups. Vascular function was assessed using coronary artery tension measurements, while BK channel activity was evaluated via whole-cell patch clamp. Primary vascular SMCs were isolated for in vitro studies. SPD-binding proteins were identified through pull-down assays coupled with LC-MS/MS analysis. RESULTS: SPD treatment improved coronary BK channel-dependent vasorelaxation by up-regulating BK-β1 subunit expression. Mechanistically, SPD directly bound to pyruvate kinase M2 (PKM2), inhibiting PKM2 nuclear translocation and subsequent signal transducer and activator of transcription 3 (STAT3) activation. Furthermore, STAT3 transcriptionally regulated F-box protein 32 (FBXO32), which modulated BK-β1 expression. CONCLUSIONS: SPD protects BK channel function in diabetic conditions through inhibition of the PKM2/STAT3 signaling axis, revealing a novel therapeutic pathway for diabetic vascular complications. However, given the exploratory experimental nature of this study, these findings should be considered hypothesis-generating and require further validation in independent studies.
Reassessing the role of PPARgamma in vascular effects of cannabinoids: A critical appraisal.
Panasiuk O, Kavertseva M, Goswami N … +1 more , Bondarenko AI
Vascul Pharmacol · 2026 Jun · PMID 42288170 · Publisher ↗
This focused review provides a critical narrative appraisal of the mechanisms underlying cannabinoid-induced vascular effects, with particular emphasis on cannabinoid receptor- and PPARgamma-independent pathways, as well...
This focused review provides a critical narrative appraisal of the mechanisms underlying cannabinoid-induced vascular effects, with particular emphasis on cannabinoid receptor- and PPARgamma-independent pathways, as well as on ion channel modulation. Priority was given to studies providing mechanistic insights into vascular signaling pathways mediating the vasodilator effects of cannabinoids and commonly used PPARgamma ligands. The available experimental evidence supporting a role for PPARgamma in the vascular actions of cannabinoids is critically evaluated. Given the partially overlapping pharmacological profiles of cannabinoids and commonly used PPARgamma ligands, together with the lack of direct evidence demonstrating that PPARgamma itself, rather than off-target effects of its ligands, is responsible for vasodilation, the proposed role of PPARgamma in cannabinoid-induced vascular effects should be interpreted with caution. Definitive validation of PPARgamma involvement in the vascular effects of cannabinoids requires complementary approaches, including the use of genetic animal models, targeted manipulation of PPARgamma, and the use of highly selective ligands.
Integrated multi-omics and experimental validation reveal CSK and FBLN1 as key targets of stanozolol in accelerating atherosclerosis.
Li R, Zhang R, Liu J … +1 more , Tang Y
Vascul Pharmacol · 2026 Jun · PMID 42250865 · Publisher ↗
BACKGROUND: Stanozolol, a synthetic anabolic androgenic steroid (AAS) widely abused to enhance performance, has poorly defined toxicological mechanisms in atherosclerosis (AS). METHODS: An AS model was established in Apo...
BACKGROUND: Stanozolol, a synthetic anabolic androgenic steroid (AAS) widely abused to enhance performance, has poorly defined toxicological mechanisms in atherosclerosis (AS). METHODS: An AS model was established in ApoE/ mice, followed by a 12-week stanozolol intervention. Effects on lipid metabolism, systemic inflammation, and plaque formation were assessed. Potential targets were predicted via database integration. Transcriptomic analyses included differential expression, WGCNA, GSEA, CIBERSORT, and single-cell RNA-seq. Core toxic targets were identified using LASSO, SVM-RFE, and random forest. Validation was performed by qRT-PCR, Western blotting, and immunofluorescence. Molecular docking and 100-ns MD simulations were conducted to assess binding affinity and stability. RESULTS: Stanozolol significantly aggravated AS progression, marked by increased lipid deposition, vascular remodeling, dyslipidemia, and systemic inflammation. Integration of multi-omics and machine learning identified three key targets-CSK, FBLN1, and BCHE-With stable binding to stanozolol. Functional assays showed CSK upregulation in macrophages and FBLN1 downregulation in vascular smooth muscle cells. CONCLUSION: Stanozolol accelerates atherosclerosis by activating inflammatory responses and disrupting vascular homeostasis. CSK and FBLN1 are core toxic mediators and potential therapeutic targets.
Genomic and proteogenomic insights into Spontaneous Coronary Artery Dissection (SCAD): A systematic review of emerging multi-omic evidence.
Russo A, Alberti M, Biondi F … +4 more , Aquaro GD, Morrone D, Madonna R, De Caterina R
Vascul Pharmacol · 2026 Jun · PMID 42250864 · Publisher ↗
BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a major cause of myocardial infarction in young women without traditional cardiovascular risk factors (Hayes et al., 2018; Adlam et al., 2018 [1, 2]). Despite...
BACKGROUND: Spontaneous coronary artery dissection (SCAD) is a major cause of myocardial infarction in young women without traditional cardiovascular risk factors (Hayes et al., 2018; Adlam et al., 2018 [1, 2]). Despite growing awareness, its biological underpinnings remain incompletely understood, and clinical management is largely based on observational evidence rather than mechanistic insight (Saw et al., 2014; Lettieri et al., 2015; Steg et al., 2024 [3-5]). OBJECTIVES: To systematically integrate genomic, epitranscriptomic, proteomic, and metabolomic data in order to characterize the multi-omic architecture of SCAD and identify potential biomarkers and therapeutic targets. METHODS: A systematic review was conducted in accordance with the PRISMA 2020 statement (Arbelo et al., 2023 [6]). PubMed/MEDLINE was searched for original studies investigating genomic and multi-omic features of SCAD. Data were extracted on study design, patient characteristics, identified variants, circulating biomarkers, and implicated biological pathways. Functional enrichment analysis was performed using the DAVID bioinformatics resource (Page et al., 2021 [7]). RESULTS: A total of 16 studies were included. Genome-wide association studies consistently identified susceptibility loci related to arterial structure and extracellular matrix integrity, including ADAMTSL4, PHACTR1/EDN1, LRP1, and FBN1 (Huang et al., 2009; Saw et al., 2020; Turley et al., 2020 [8-10]). Rare variant analyses further supported the role of genes involved in extracellular matrix remodeling and vascular smooth muscle cell function, including COL3A1, COL4A1/2, SMAD3, and TLN1 (Adlam et al., 2023; Turley et al., 2021, 2019; Carss et al., 2020; Zekavat et al., 2022; Wang et al., 2022 [11-16]), while ancestry-specific signals such as TSR1 variants were observed in distinct populations (Turley et al., 2023 [17]). Proteogenomic approaches linked genetic susceptibility loci to circulating proteins involved in matrix remodeling and inflammation, including cathepsin B and ECM1 (Maioli et al., 2010 [18]). Epitranscriptomic analyses identified differential microRNA expression profiles associated with vascular injury and repair pathways (Sun et al., 2019 [19]). CONCLUSIONS: SCAD is characterized by a complex, multi-layered biological architecture involving genetic susceptibility, extracellular matrix dysregulation, and vascular signaling pathways. Integration of multi-omic data provides novel insights into disease mechanisms and highlights potential biomarkers and targets for precision medicine approaches in SCAD.
Cardiac magnetic resonance in patients with acute myocardial infarction: The added clinical value.
Alberti M, Faggioni L, Cioni D … +4 more , Neri E, Madonna R, De Caterina R, Aquaro GD
Vascul Pharmacol · 2026 Jun · PMID 42250863 · Publisher ↗
Cardiovascular magnetic resonance (CMR) has emerged as the reference noninvasive modality for a comprehensive assessment of myocardial injury following acute myocardial infarction (AMI). Beyond accurate quantification of...
Cardiovascular magnetic resonance (CMR) has emerged as the reference noninvasive modality for a comprehensive assessment of myocardial injury following acute myocardial infarction (AMI). Beyond accurate quantification of ventricular volumes and ejection fraction, CMR uniquely enables in vivo characterization of the infarct size, the ischemic area at risk, microvascular obstruction, intramyocardial hemorrhage, and interstitial remodeling-pathophysiological processes that are all tightly linked to adverse left ventricular remodeling and long-term clinical outcomes. Advances in late gadolinium enhancement imaging and parametric mapping techniques, including native T1, T2, T2*, and extracellular volume quantification, have now expanded the ability of CMR to capture both irreversible myocardial necrosis and dynamic inflammatory injury within the infarcted and the remote myocardium. Importantly, these imaging biomarkers provide prognostic information incremental to conventional clinical parameters and have become central to risk stratification, etiologic diagnosis in myocardial infarction with non-obstructive coronary arteries (MINOCA), and surrogate endpoint selection in cardioprotective clinical trials. This review provides a contemporary overview of the role of CMR in AMI, with emphasis on optimal timing, pragmatic protocol design, infarct severity phenotyping, post-infarction complications, and risk stratification beyond ejection fraction. Emerging developments, including accelerated imaging, artificial intelligence-assisted analysis, low-field systems, and complementary integration with cardiac computed tomography, are discussed as key drivers shaping the future clinical implementation of CMR in ischemic heart disease.
N6-methyladenosine (m6A) post-transcriptional modification regulation of mRNA, an overlooked therapeutic opportunity to leverage mRNA processing in vascular smooth muscle cells.
Openko D, Autieri MV
Vascul Pharmacol · 2026 Jun · PMID 42176928 · Full text
In response to pathological stimuli, VSMCs modulate from a quiescent, contractile phenotype to a synthetic, non-contractile phenotype with increased migration, proliferation, and expression of matrix and pro-inflammatory...
In response to pathological stimuli, VSMCs modulate from a quiescent, contractile phenotype to a synthetic, non-contractile phenotype with increased migration, proliferation, and expression of matrix and pro-inflammatory cytokines. This response necessitates modification in expression of a plethora of mRNA transcripts, which often requires fine-tuning by post-translational changes in the stability of these mRNAs. N6-methyladenosine (m6A) modification can affect the fate of many mRNA transcripts in the cell, especially mRNA stability. Various m6A regulatory proteins, such as writers (methylases), erasers (demethylases), and readers (RNA binding proteins) are involved in various homeostatic processes in the cell, and can become dysregulated in disease states, contributing to vascular pathology. Recently, it has been shown that these m6A modulatory proteins can be targeted therapeutically with small molecule inhibitors to alter their expression and activity in the cell, opening up the possibility that targeting modifiers of the mRNA methylome can be leveraged as a therapeutic opportunity to treat vascular diseases. This review describes the mechanisms and explores roles of m6A modification in mRNA processing and how these changes in the VSMC transcriptome can contribute to pathogenesis and possibly treatment of vascular diseases.
CaMKIIδ splice variants differentially regulate vascular smooth muscle cell motility.
O'Brien BJ, Mistretta S, Sun L … +3 more , Singer DV, Ginnan R, Singer HA
Vascul Pharmacol · 2026 Jun · PMID 42155796 · Publisher ↗
Vascular smooth muscle (VSM) cell migration promotes physiological and pathophysiological vascular remodeling. A previous study from our laboratory demonstrated that both CaMKIIδ and FYN, a SRC- family kinase, promote VS...
Vascular smooth muscle (VSM) cell migration promotes physiological and pathophysiological vascular remodeling. A previous study from our laboratory demonstrated that both CaMKIIδ and FYN, a SRC- family kinase, promote VSM cell migration in vitro. CaMKIIδ co-localized with FYN and physically interacted in an activation-dependent manner, with CaMKIIδ activation resulting in FYN activation and dissociation of the interaction. The CAMK2D gene undergoes extensive alternative splicing, including an exon encoding a 21-amino acid C-terminus, resulting in the expression of CaMKIIδ and related variants that include the 21-AA C-terminal tail, and CaMKIIδ and related variants lacking the sequence. The aforementioned CaMKIIδ/FYN interaction was attributed to the CaMKIIδ variant that predominates in rat aortic VSM cells used in those studies. The purpose of this study was to test the functional equivalency of CaMKIIδ and CaMKIIδ isoforms in mediating signal transduction required for VSM motility. Adenoviral overexpression of CaMKIIδ inhibited VSM cell motility, disrupted CaMKIIδ/FYN interaction reduced localization of active CaMKIIδ in lamellipodia, and reduced PDGF-dependent tyrosine phosphorylation of the focal adhesion proteins, P130 and paxillin mediated by FYN. Silencing FYN expression using siRNA phenocopied these effects of over-expressing CaMKIIδ. As an alternative approach, application of an exon skipping antisense oligonucleotide targeting the C-terminal exon in the Camk2d gene, resulted in loss of CaMKIIδ expression and a reciprocal increase in expression of CaMKIIδ. This manipulation of endogenous CaMKIIδ variant expression also inhibited localization of active CaMKIIδ in lamellipodia and inhibited VSM cell migration. Taken together, these results suggest that the alternatively spliced C-terminal domain in the CaMKIIδ splice variant confers interaction with FYN, localization of the kinases to lamellipodia, and consequent regulation of focal adhesion dynamics to promote VSM cell migration.
Endothelium- selective overexpression of p25 results in impaired smooth muscle-dependent vascular function, altered sGC-dependent pathway, and vascular remodeling.
Sternak M, Wang P, Bar A … +6 more , Kieronska-Rudek A, Kurylowicz Z, Jasztal A, Kij A, Wang Y, Chlopicki S
Vascul Pharmacol · 2026 Jun · PMID 42155795 · Publisher ↗
The role of P25 is dual, acting as a critical, transient regulator in normal memory formation, but also causes patological effect as a neurotoxic agent when activated chronically in neurodegenerative diseases. However, t...
The role of P25 is dual, acting as a critical, transient regulator in normal memory formation, but also causes patological effect as a neurotoxic agent when activated chronically in neurodegenerative diseases. However, the role of CDK5/p25 signaling in endothelium has not been established. Here, we assessed the effect of selective endothelial overactivation of p25, the major regulator of the CDK5 on vascular function. In transgenic mouse model with selective overexpression of P25 in vascular endothelial cells (EC-p25) endothelial and smooth muscle function was characterized in vivo using unique MRI-based analysis, with accompanying molecular and biochemical assays in isolated vessels and endothelial cells. In young 12-20 week-old EC-p25 mice Ach-induced vasodilation measured in vivo by MRI was lost and changed into vasoconstriction. Flow-mediated vasodilation (FMD) was progressively impaired in 12-20 week-old EC-p25 mice. SNP-induced vasodilation was also profoundly impaired. Moreover, it was associated with vascular smooth muscle cells (VSMC) remodeling including hyperplasia and hypertrophy of smooth muscle cells as well as deposition of extracellular matrix (ECM). Nitric oxide production in aorta ex vivo assessed by EPR, NOS expression assessed by immunohistological staining, as well systemic NO bioavailability assessed based on nitrite and nitrate plasma concentration measured by HPLC were all not significantly changed in 12-20 week-old EC-p25 mice. However, aorta from 20-week-old EC-p25 mice displayed diminished α-SMA and sGC expression. In conclusion, endothelium-specific p-25 overexpression resulted in impaired smooth muscle - dependent vascular function and altered sGC-dependent pathway that was correlated with altered structure of aortic wall. Altogether, the overexpression of p-25 -dependent endothelial signaling resulted in dysregulation of VSMC structure and function highlighting disturbance in EC-VSMC communication.
Right Ventricular-Pulmonary Arterial Coupling and Exercise-induced Pulmonary Congestion in Heart Failure with Reduced and Mildly-reduced Ejection Fraction.
Mazzola M, Michelotti E, De Biase N … +4 more , Grassini D, Bort IR, Pugliese NR, Gargani L
Vascul Pharmacol · 2026 Jun · PMID 42150627 · Publisher ↗
AIMS: We explored the relationship between right ventricular-pulmonary arterial (RV - PA) coupling and exercise pulmonary congestion in heart failure patients with reduced (HFrEF) and mildly reduced (HFmrEF) left ventric...
AIMS: We explored the relationship between right ventricular-pulmonary arterial (RV - PA) coupling and exercise pulmonary congestion in heart failure patients with reduced (HFrEF) and mildly reduced (HFmrEF) left ventricle ejection fraction. METHODS AND RESULTS: A cohort of 118 HFrEF and HFmrEF patients underwent baseline transthoracic echocardiography and exercise stress echocardiography (ESE), assessing extravascular lung water (EVLW) changes through lung ultrasound (LUS) B-lines. The TAPSE/PAPs ratio served as RV - PA coupling surrogate. Compared to patients with ∆B-lines ≤10, those with ∆B-lines >10 displayed a worse RV-PA coupling both at rest (median TAPSE/PAPs: 0.77 mm/mmHg vs 0.57 mm/mmHg, p = 0.002) and at peak exercise (median TAPSE/PAPs: 0.58 mm/mmHg vs 0.39 mm/mmHg, p < 0.001). Worsening RV - PA coupling at peak effort inversely correlated with exercise extravascular lung water increase, but only in patients with higher peak PAPs (peak PAPs 4255 mmHg; r = 0.53, p = 0.001). CONCLUSION: Exercise may induce impairments in RV-PA coupling which hampers lung lymphatic drainage through elevated central venous pressure and increases EVLW. This is especially true for patients with higher peak PAPs values, in which a significant increase in capillary pressure during exercise can occur in absence of the structural pulmonary alterations observed in more advanced stages of HF.
The role of the endothelium in long COVID.
Tamariz L, Shehadeh LA, Bast E … +2 more , Klimas N, Palacio A
Vascul Pharmacol · 2026 Jun · PMID 42140539 · Publisher ↗
SARS-CoV2 infection significantly increases the risk of cardiovascular events through multiple interconnected mechanisms including systemic inflammation, dysautonomia, endothelial dysfunction, and prothrombotic states. T...
SARS-CoV2 infection significantly increases the risk of cardiovascular events through multiple interconnected mechanisms including systemic inflammation, dysautonomia, endothelial dysfunction, and prothrombotic states. The endothelium plays a critical role in this increase in risk together with dysautonomia and mast cell activation. SARS-CoV2 activates endothelial cells creating a pro-inflammatory, and pro-thrombotic phenotype. This phenotype could lead to microcirculatory changes that decrease oxygen delivery to tissues because of loss of laminar flow, lack of nitric oxide dependent vasodilation, increased viscosity and abnormal constriction of vascular smooth muscle cells due to neuropathy. There are several ways of identifying patients with endothelial dysfunction and the most used is flow mediated dilation. Many randomized trials have already found significant treatments for endothelial dysfunction and include antihypertensives, statins, beta-blockers, supplements and lifestyle interventions. Only two studies using vitamin C and L-arginine demonstrated improvements in flow mediated dilation in patients with long COVID.
Brain natriuretic peptide as a potential predictor of hemorrhagic transformation in acute ischemic stroke patients with successful endovascular recanalization: A two-center retrospective cohort study.
Yang L, Cheng C, Miao W … +6 more , Huang W, Zhang Q, Zhu Y, Sun J, Shao J, Luan D
Vascul Pharmacol · 2026 Jun · PMID 42097247 · Publisher ↗
Hemorrhagic transformation (HT) remains a critical complication following successful endovascular recanalization in acute ischemic stroke (AIS), contributing to adverse clinical outcomes. This two-center retrospective co...
Hemorrhagic transformation (HT) remains a critical complication following successful endovascular recanalization in acute ischemic stroke (AIS), contributing to adverse clinical outcomes. This two-center retrospective cohort study, designed as an exploratory, hypothesis-generating investigation, aimed to preliminarily explore the potential role of brain natriuretic peptide (BNP) as a predictor of HT in AIS patients with successful endovascular recanalization, and to generate testable hypotheses for subsequent clinical validation. A total of 128 eligible patients were enrolled, including 47 in the HT group and 81 in the non-HT group. Postoperative BNP levels, clinical data, and imaging findings were analyzed. Results showed that postoperative BNP levels were significantly elevated in the HT group compared with the non-HT group (396.46 ± 594.97 vs. 200.74 ± 213.63 pg/ml, P = 0.003). Univariate and multivariate logistic regression analyses demonstrated that BNP was an independent predictor of HT (adjusted OR = 1.002, 95% CI: 1.000-1.004, P = 0.048) after adjusting for confounding factors. The area under the receiver operating characteristic curve (AUC) for the fully adjusted model (Model 6) was 0.713 (95% CI: 0.620-0.806), indicating good discriminative ability. A nomogram incorporating BNP and other variables showed favorable calibration for predicting HT risk. Mechanistically, integrative analyses of BNP's 3D structure, gene-level networks, and protein interactions revealed its involvement in vascular homeostasis, cardiac function, and inflammation-key pathways in HT pathogenesis. In conclusion, this hypothesis-generating study provides preliminary exploratory evidence that postoperative BNP is a potential predictive biomarker of HT in AIS patients with successful endovascular recanalization. Our findings generate a testable clinical hypothesis for future validation, with potential clinically relevant value for risk stratification and personalized clinical management after prospective confirmation.
Decreased exercise-induced pulmonary capillary recruitment in pulmonary arterial hypertension.
Langleben D, Orfanos SE, Fox BD … +3 more , Giovinazzo M, Kaddis M, Catravas JD
Vascul Pharmacol · 2026 Jun · PMID 42086100 · Publisher ↗
The human lung normally accommodates exercise-induced cardiac output increases mainly via recruitment of non-concomitantly perfused pulmonary capillaries. Recruitment is detectable by measuring the first-pass transpulmon...
The human lung normally accommodates exercise-induced cardiac output increases mainly via recruitment of non-concomitantly perfused pulmonary capillaries. Recruitment is detectable by measuring the first-pass transpulmonary metabolism of H-benzoyl-Phe-Ala-Pro, providing an estimate of functional capillary surface area (FCSA). Pulmonary arterial hypertension (PAH) results from luminal narrowing of small precapillary arterioles, reducing downstream perfused FCSA. We hypothesized that exercising PAH patients would not be able to recruit FCSA normally. We studied two patients with severe PAH. Despite exercising to maximal dyspnea, neither could recruit FCSA. These limited data are the first direct measurements of FCSA in exercising PAH patients.
Chronic venous insufficiency and cardiovascular risk: Marker or bystander?
Mauriello A, Correra A, Del Guercio M … +5 more , Caturano A, Riegler L, Pastore F, D'Andrea A, Russo V
Vascul Pharmacol · 2026 Jun · PMID 42086099 · Publisher ↗
Chronic Venous Insufficiency (CVI) is a complex condition resulting from venous valve dysfunction or a loss of structural integrity in the vein walls, affecting 60% of the general population. Although traditionally regar...
Chronic Venous Insufficiency (CVI) is a complex condition resulting from venous valve dysfunction or a loss of structural integrity in the vein walls, affecting 60% of the general population. Although traditionally regarded as a localized peripheral pathology, emerging evidence suggests that CVI may serve as an early indicator of systemic vascular disease. Our comprehensive review aims to analyzes the pathophysiological links between CVI and global cardiovascular risk, evaluating the clinical impact of venous disease on cardiovascular morbidity and mortality. The current literature highlights shared mechanisms between CVI and arterial diseases, including chronic low-grade inflammation, oxidative stress, and endothelial dysfunction. Clinical studies indicate that CVI is an independent predictor of major adverse cardiovascular events (MACE) and all-cause mortality. CVI should be reinterpreted as a peripheral marker of systemic vascular frailty. The integration of proactive cardiovascular screening is proposed for the management of patients with advanced CVI to improve long-term prognosis and reduce the risk of fatal events.
Single-cell lineage tracing unveils sex differences in VSMCs derived from the cardiac neural crest and second heart field.
Wang Y, Luo C, Wang S … +3 more , Li L, Fu K, Lyu QR
Vascul Pharmacol · 2026 Jun · PMID 42069076 · Publisher ↗
Stanford type A thoracic aortic aneurysm and dissection (TAAD) affects the ascending aorta and aortic arch and can cause sudden death due to rupture. Epidemiological studies have shown that TAAD occurs more frequently in...
Stanford type A thoracic aortic aneurysm and dissection (TAAD) affects the ascending aorta and aortic arch and can cause sudden death due to rupture. Epidemiological studies have shown that TAAD occurs more frequently in men than women. Vascular smooth muscle cells (VSMCs) are one of the major cell types in the vascular wall and play a critical role in the pathogenesis of TAAD. Recent studies have highlighted the developmental heterogeneity of VSMCs in the ascending aorta and aortic arch, which are derived primarily from the second heart field (SHF) and cardiac neural crest (CNC), respectively. However, whether sex influences the biological properties of these lineage-specific VSMCs and thereby contributes to TAAD susceptibility remains poorly understood. In this study, we generated Wnt1-Cre/Rosa26-mTmG lineage-tracing reporter mice and performed single-nucleus RNA sequencing using the ascending aortae and aortic arch from both sexes. Our results showed that male VSMCs exhibited higher expression of genes associated with maintenance of contractility, whereas female VSMCs preferentially expressed genes involved in extracellular matrix (ECM) organization. Together, these data suggest that the ascending aorta and aortic arch in females may exhibit greater mechanical resilience, which partially account for the lower incidence of TAAD in women.
Venoactive drugs in the management of chronic venous disease: A critical appraisal of the evidence and comparison with international guidelines.
Santiago FR, Grillo L, Amore M … +3 more , Carmelino C, Trejo JMR, Ulloa JH
Vascul Pharmacol · 2026 Jun · PMID 42066876 · Publisher ↗
Chronic venous disease (CVD) is a prevalent condition that results from venous hypertension and leads to a variety of symptoms including leg pain, swelling, and venous ulcers. The condition significantly impacts quality...
Chronic venous disease (CVD) is a prevalent condition that results from venous hypertension and leads to a variety of symptoms including leg pain, swelling, and venous ulcers. The condition significantly impacts quality of life (QoL) and imposes a burden on healthcare systems. Venoactive drugs (VADs) can manage CVD symptoms by improving venous tone, reducing inflammation, and enhancing microcirculation. In this review, six experts from Latin America provide a critical appraisal of the evidence supporting the use of VADs in CVD management. The review evaluates the efficacy of various VADs, including micronized purified flavonoid fraction (MPFF), rutosides, calcium dobesilate, sulodexide, horse chestnut seed extract, and red vine leaf extract. MPFF demonstrated robust efficacy in randomized controlled trials, significantly reducing symptoms such as pain, leg heaviness, and edema, and improving QoL. Other VADs, such as rutosides and calcium dobesilate, showed varying degrees of effectiveness, though the quality of supporting evidence remains inconsistent. This review also highlights variations in international guidelines - some recommending VADs more strongly than others, with MPFF emerging as the preferred option, supported by high-quality evidence. However, further research is necessary to clarify the role of other VADs and provide more definitive guidance on their use in clinical practice. PLAIN LANGUAGE SUMMARY: Chronic venous disease (CVD) is a condition that affects the veins in the legs, causing pain, swelling, and other symptoms like heaviness and cramping. It can also lead to more severe issues such as skin changes and ulcers. CVD is common and can greatly reduce a person's quality of life (QoL). It can also place a significant burden on healthcare systems. Venoactive drugs, or VADs, are medicines that help improve blood flow in the veins, reduce swelling, and ease inflammation. These drugs are used to alleviate CVD symptoms, especially when other conservative treatments, like compression stockings, are insufficient. This review describes the published evidence about different types of VADs and their effectiveness in CVD. Some drugs, like micronized purified flavonoid fraction (MPFF), have been shown to be particularly effective in reducing leg pain, swelling, and heaviness, as well as helping to improve the QoL of people with CVD. Other VADs, including rutosides, calcium dobesilate, and horse chestnut seed extract, have demonstrated clinical efficacy. Different medical guidelines for treating CVD from around the world recommend using VADs, though with some discrepancies on recommendation gradings. While MPFF is referred to in these guidelines as a leading option, further research is needed to better understand how different VADs can be used most effectively in treating CVD.
Clinical characteristics and five-year outcomes in a prospective Russian real-world heart failure cohort.
Pogosova N, Terteryan T, Avagimyan A … +7 more , Arutyunov A, Popova A, Vorobyeva N, Osipova I, Zhetisheva R, Ausheva A, Madonna R
Vascul Pharmacol · 2026 Jun · PMID 42061780 · Publisher ↗
BACKGROUND: Despite advances in therapy, data on long-term survival and temporal mortality patterns in real-world heart failure (HF) populations, particularly during the critical early period after diagnosis or clinical...
BACKGROUND: Despite advances in therapy, data on long-term survival and temporal mortality patterns in real-world heart failure (HF) populations, particularly during the critical early period after diagnosis or clinical destabilization, remain scarce. This study aimed to analyze long-term survival and identify factors associated with mortality in a prospective Russian real-world HF cohort that is relatively underrepresented in the international registry literature. METHODS: A prospective 5-years registry study consecutively enrolled 150 patients with HF in February-May 2018. Participants underwent comprehensive assessment of clinical state, traditional cardiovascular risk factors (RF), psychosocial RF, quality of life, perception of illness, cognitive function, and treatment characteristics. Survival was analyzed using the Kaplan-Meier method, and mortality trends were assessed over time. The Cox proportional hazard model, with calculation of hazard ratio (HR) and 95% coincidence interval (CI), was used for univariate and multivariate regression analyses. RESULTS: The cohort (median age 69 years, 57% male) was elderly and multimorbid, with high prevalence of coronary artery disease (95%), hypertension (91%), and chronic kidney disease (56%). Guideline-directed medical therapy was suboptimal: while beta-blocker and diuretic use was high (87% and 79%, respectively), utilization of aldosterone antagonists and ARNI was low (40% and 0.7%, respectively). Only 32.7% received multicomponent HF therapy. The overall 5-years (0.02-5.09) survival rate was 59.9%. Approximately half (48%) of patients died in the first year, the remaining deaths occurred in 2-nd, 3-rd and 4-th years (15%, 17%, and 20%, respectively), and deaths were recorded during 5-th and 6-th years of follow-up. Kaplan-Meier survival analysis showed that left ventricular ejection fraction (LV EF) was strongly associated with 5-years survival. In patients with reduced and moderately reduced LV EF 5-years survival was significantly lower than that in those with preserved LV EF (50.0% and 45.7% versus 70.4%, respectively). No significant difference was found only when comparing the survival curves of patients with moderately reduced and reduced LV EF (chi-square = 0.014; p = 0.906). The leading cause of death was decompensation of HF (65.2%), followed by sudden cardiac death (15.2%). Multivariate analysis showed that age (HR 1.03 per 1-year increase; 95% CI 1.01-1.06; p = 0.017), weight loss >4.5 kg in 5 days in response to therapy (HR 3.49; 95% CI 1.82-6.68; p < 0.001), anemia (HR 2.83; 95% CI 1.47-5.46; p = 0.002), obstructive sleep apnea syndrome (HR 4.43; 95% CI 1.91-10.28; p = 0.001), and HF NYHA functional class IV (HR 4.79; 95% CI 1.50-15.34; p = 0.008) were independent predictors of 5-years all-cause mortality in HF patients. CONCLUSION: This study identifies a high early mortality phenotype in a real-world HF population, strongly associated with significant gaps in guideline-directed therapy. The findings underscore the urgent need for early aggressive optimization of treatment, particularly in the high-risk period following diagnosis or destabilization of HF, to improve long-term survival.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe