Vascular pharmacology最新文献

{"title":"Leiomodin 1 haploinsufficiency promotes smooth muscle cell proliferation and increases neointimal lesion size","authors":"Sara A. Wennersten,&nbsp;Hongxia Wang,&nbsp;J. Lee Franklin,&nbsp;Vivek Nanda","doi":"10.1016/j.vph.2025.107555","DOIUrl":"10.1016/j.vph.2025.107555","url":null,"abstract":"<div><div>The transition of smooth muscle cells (SMCs) from a contractile to a synthetic phenotype is a key contributor to cardiovascular disease (CVD) pathologies, such as atherosclerosis and in-stent restenosis. We previously reported that loss of leiomodin 1 (<em>LMOD1</em>), a coronary artery disease risk gene highly expressed in SMCs, promotes SMC phenotypic switching <em>in vitro</em>. However, the <em>in vivo</em> role of LMOD1 and the molecular mechanisms driving this transition remain unknown. In this study, we found that <em>Lmod1</em> heterozygous mice subjected to carotid artery ligation developed larger neointimal lesions. Histopathological analyses attributed this phenotype to increased SMC proliferation. RNA sequencing studies of <em>LMOD1</em>-deficient SMCs revealed a significant upregulation of genes associated with increased cell proliferation, particularly those involved in the G1/S phase transition. Further analysis identified cyclin-dependent kinase 6 (CDK6) as a potential mediator of this hyperproliferative response. Notably, the knockdown of <em>CDK6</em> in <em>LMOD1</em>-deficient cultured SMCs restored SMC proliferation to near baseline levels, indicating that the observed phenotype is reversible <em>in vitro</em>. Collectively, these findings indicate that LMOD1 deficiency promotes SMC proliferation by upregulating CDK6 expression and provide mechanistic insight into how reduced LMOD1 expression may contribute to increased neointimal lesion size and vascular remodeling.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"161 ","pages":"Article 107555"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145474216","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial and non-endothelial actions of estrogen receptor subtypes in male and female mouse Aorta","authors":"Basant Elsaid ,&nbsp;Irakli Kopaliani ,&nbsp;Birgit Zatschler ,&nbsp;Ansam Seif ,&nbsp;Stephan Speier ,&nbsp;Andreas Deussen","doi":"10.1016/j.vph.2025.107559","DOIUrl":"10.1016/j.vph.2025.107559","url":null,"abstract":"<div><div>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.</div><div>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.</div><div>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.</div><div>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.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"161 ","pages":"Article 107559"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145490176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pre-eclampsia with inflammatory and pro-resolving mediator fluctuations - contributions from hemolytic protozoan parasites","authors":"Kevin Roe","doi":"10.1016/j.vph.2025.107552","DOIUrl":"10.1016/j.vph.2025.107552","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"161 ","pages":"Article 107552"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145309384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Emerging role of the adaptive immunity in aortic aneurysm and dissection","authors":"Yan-Ni Hu ,&nbsp;Mi Wang ,&nbsp;Zheng Zhang","doi":"10.1016/j.vph.2025.107558","DOIUrl":"10.1016/j.vph.2025.107558","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"161 ","pages":"Article 107558"},"PeriodicalIF":3.5,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145483046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of histone modifications in pulmonary hypertension: From mechanisms to therapeutic targets","authors":"Yunhua Yang ,&nbsp;Shaoxin Gong ,&nbsp;Na Liang ,&nbsp;Zhouxin Li ,&nbsp;Xiaoyu Duan ,&nbsp;Tong Xie ,&nbsp;Xiaoyong Lei ,&nbsp;Aiping Wang","doi":"10.1016/j.vph.2025.107519","DOIUrl":"10.1016/j.vph.2025.107519","url":null,"abstract":"<div><div>Pulmonary hypertension is a progressive vascular disease characterized by pulmonary vascular remodeling, with high mortality and poor prognosis despite advances in medical therapy. Recently, histone modification therapies for pulmonary hypertension have received more attention. Studies have shown that abnormal histone modifications and the enzymes responsible for these alterations can drive pulmonary vascular cell proliferation, migration, and anti-apoptosis by regulating chromatin structure and gene expression, thereby promoting pulmonary vascular remodeling in pulmonary hypertension. This review illustrates histone modifications, including methylation, acetylation, lactylation, and SUMOylation, and the enzymes responsible for these modifications, exploring their role and pathophysiological mechanism in pulmonary hypertension. In addition, the review summarizes the small molecule modulators currently under development and their efficacy in various preclinical models of pulmonary hypertension. Comprehending the function of histone modifications in pulmonary hypertension will help identify new biomarkers and molecular targets and facilitate personalized treatments for this severe disease.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107519"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144512583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics identification of quantitative trait loci associated with vascular pathogenesis and diagnostic potential in chronic venous disease","authors":"Cheng-Hsun Chuang ,&nbsp;Hsiao-Hsuan Huang ,&nbsp;Yi-Syuan Wu ,&nbsp;Nien-Che Ho ,&nbsp;Chi-Ting Huang ,&nbsp;Yi-Chen Huang ,&nbsp;Hsien-Da Huang ,&nbsp;Shun-Long Weng ,&nbsp;Meng-Lin Lee ,&nbsp;Kuang-Wen Liao","doi":"10.1016/j.vph.2025.107532","DOIUrl":"10.1016/j.vph.2025.107532","url":null,"abstract":"<div><div>Chronic venous disease (CVD) is a prevalent vascular disorder with a poorly characterized genetic basis. In this study, we employed an integrative omics strategy combining genome-wide association studies (GWAS), expression quantitative trait loci (eQTL) mapping, endothelial cell functional assays, and transcriptomic correlation analysis to elucidate the molecular architecture of CVD. A GWAS conducted in a Taiwanese population identified two CVD-associated single nucleotide polymorphisms: VSTM2L rs1998049 and DPYSL2 rs1442887. Through eQTL analysis and endothelial functional assays, four QTLs (<em>VSTM2L</em>, <em>RPRD1B</em>, <em>SAMHD1</em>, and <em>PNMA2</em>) were found to significantly affect VEGF consumption, vWF expression, and endothelial tube formation. Co-expression and correlation analyses further linked these QTLs to key vascular effector genes, including <em>VEGF</em>, <em>vWF</em>, <em>MMP9</em>, and <em>CCM2</em>. A logistic regression model based on QTL expression profiles demonstrated high diagnostic performance (area under the curve, AUC = 0.898), highlighting their translational potential. These findings offer novel insights into the functional genomics of CVD, particularly in relation to vascular remodeling, endothelial dysfunction, and inflammation. They also demonstrate the utility of multi-omics integration for biomarker discovery in complex vascular disorders.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107532"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antagonism of the complement receptor reduces oxidative stress and matrix metalloproteinase (MMP)-2 activity in the aortas of mice with angiotensin-II-induced hypertension","authors":"Luan Victor Resque Ramos,&nbsp;Marcela M. Blascke de Mello,&nbsp;Bruno Marcel Silva de Melo,&nbsp;José Teles de Oliveira Neto,&nbsp;Evellin Karina Pires Bueno,&nbsp;José Carlos Farias Alves Filho,&nbsp;Rita Tostes,&nbsp;Michele M. Castro","doi":"10.1016/j.vph.2025.107523","DOIUrl":"10.1016/j.vph.2025.107523","url":null,"abstract":"<div><div>Angiotensin II (Ang II) increases C3a effects through its receptors, promoting aortic oxidative stress and upregulating matrix metalloproteinase (MMP)-2. MMP-2 is implicated in hypertrophic arterial remodeling in hypertension. This study investigated whether C3a receptor activation contributes to oxidative stress and increased MMP-2 activity in aortas of Ang II treated mice, ultimately leading to maladaptive vascular changes. Hypertension was induced in C57BL/6 mice via subcutaneous implantation of osmotic mini pumps delivering Ang II (1000 ng/kg/min) for 14 days. Mice were administered the C3aR antagonist, SB290157 (1 mg/kg/day, intraperitoneally) every other day for 14 days. Systolic blood pressure (SBP) and vascular function were assessed via direct blood pressure measurements and contraction and relaxation analysis in a wire myography. Aortic MMP-2 activity was analyzed by gel and in situ zymography. SB290157 did not decrease SBP, aortic hypertrophy or increased aortic reactivity to phenylephrine in Ang II treated mice. Ang II exhibited higher levels of C3a in the plasma and increased tumor necrose factor (TNF)-α and interleukin (IL)-6 in the kidneys (*<em>p</em> &lt; 0.05). SB290157 did not alter C3a, but reduced TNF-α and IL-6 in hypertension (#<em>p</em> &lt; 0.05 vs. Ang II). SB290157 also decreased aortic oxidative stress and p65 factor nuclear kappa B (NFkB) in Ang II treated mice (*<em>p</em> &lt; 0.05). MMP-2 activity was increased in the aortas of Ang II (*<em>p</em> &lt; 0.05) and SB290157 decreased it (*<em>p</em> &lt; 0.05). Pharmacological antagonism of C3a receptor attenuates oxidative stress and MMP-2 activity in the aortas of Ang II treated mice.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107523"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144675953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational aspects of doxorubicin-induced cardiotoxicity: What we have omitted for the past decades?","authors":"Ashot Avagimyan ,&nbsp;Rosalinda Madonna ,&nbsp;Mohammad Sheibani ,&nbsp;Nana Pogosova ,&nbsp;Artem Trofimenko ,&nbsp;Olga Urazova ,&nbsp;Laura Iop ,&nbsp;Zinaida Jndoyan ,&nbsp;Hasmik Yeranosyan ,&nbsp;Anahit Aznauryan ,&nbsp;Karmen Sahakyan ,&nbsp;Anna Petrosyan ,&nbsp;Ruzanna Petrosyan ,&nbsp;Marina Tatoyan ,&nbsp;Gayane Mkrtchyan ,&nbsp;Elina Sulemaniayants ,&nbsp;Goarik Meltonyan ,&nbsp;Aleh Kuzniatsou ,&nbsp;Rupak Mukherjee ,&nbsp;Aysa Rezabakhsh ,&nbsp;Nizal Sarrafzadegan","doi":"10.1016/j.vph.2025.107526","DOIUrl":"10.1016/j.vph.2025.107526","url":null,"abstract":"<div><div>Anthracyclines remain the cornerstone of treatment for malignancies with dose-dependent cardiac damage, ranging from oxidative stress and mitochondrial dysfunction to DNA damage and ferroptosis, and continue to compromise patient outcome.</div><div>Animal models, encompassing rodents, rabbits, pigs, and nonhuman primates, are essential for investigating doxorubicin (DOX)-induced cardiovascular toxicity. Acute models facilitate rapid evaluation of cardiac injury; however, they frequently fail to replicate chronic human cardiomyopathy. In contrast, chronic models represent clinical scenarios more accurately but encounter logistical challenges. Species-specific variations in drug metabolism, cardiac physiology, and compensatory mechanisms further complicate the extrapolation. The primary limitations of existing models include the absence of comorbid conditions, lack of combination chemotherapy protocols, and underrepresentation of sex- and age-specific responses. Addressing these challenges is crucial for the development of effective and personalized cardioprotective strategies in cardio-oncology.</div><div>This review explores the translational challenges of DOX-induced cardiotoxicity, a critical limitation in the development of new cardioprotective strategies in cardio-oncology despite decades of research. We will elucidate the underlying factors that contribute to the difficulties in translating experimental in vivo results into clinical applications.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107526"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144711467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Changes in circulating lipopolysaccharide and zonulin following acute myocardial infarction: The impact of smoking","authors":"Rafał Kolec ,&nbsp;Michał Słaboszewski ,&nbsp;Elżbieta Paszek ,&nbsp;Mateusz Baran ,&nbsp;Anetta Undas","doi":"10.1016/j.vph.2025.107522","DOIUrl":"10.1016/j.vph.2025.107522","url":null,"abstract":"<div><h3>Background</h3><div>Serum lipopolysaccharide (LPS), a marker of gut dysbiosis and endotoxemia is associated with myocardial infarction (MI). We investigated factors affecting LPS changes in MI patients treated with percutaneous coronary intervention (PCI) and aimed to establish factors associated with the degree of LPS decrease following MI.</div></div><div><h3>Methods</h3><div>In 46 PCI-treated MI patients (mean age 57.2 [8.6]) years we measured LPS and zonulin, a marker of gut permeability, on admission, 30 and 60 days thereafter, inflammatory markers (interleukin [IL]-6, IL-18), P-selectin, and 8-isoprostaglandin F_2α (8-isoPGF_2α).</div></div><div><h3>Results</h3><div>The median initial LPS concentration was 44.0 (37.0–57.0) pg/mL and it fell by 11.3 % at 1 month, with a further 8.3 % drop after the second month, in association with zonulin, but not with P-selectin or inflammatory markers. LPS and zonulin at baseline correlated positively with 8-isoPGF_2α. A &lt; 10 % decrease in LPS was recorded in 20 (43.5 %) patients and was more frequent in smokers, those with a complete occlusion of the infarct-related artery (IRA) and a shorter symptom duration before PCI. LPS decrease &lt;10 % was associated with a decline in IL-10 concentrations 30- and 60-days post MI. On multivariate analysis only current smoking and an initial complete IRA occlusion were independently associated with &lt;10 % decrease in LPS at 1 month (OR 10.44; 95 % CI 2.13–51.21; <em>p</em> = 0.004 and OR 6.59; 95 % CI 1.21–35.88; <em>p</em> = 0.029, respectively).</div></div><div><h3>Conclusions</h3><div>This study is the first to show factors affecting post-MI changes in LPS, highlighting the role of smoking and initial complete IRA occlusion in persistent low-grade endotoxemia following MI.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107522"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144657095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular diameter determines sensitivity to soluble guanylate cyclase activation in human mesenteric and renal arteries","authors":"Lubomir T. Lubomirov ,&nbsp;Simon Jasinski-Bergner ,&nbsp;Kangbo Li ,&nbsp;Doris Metzler ,&nbsp;Tatiana Korotkova ,&nbsp;Jürgen Hescheler ,&nbsp;Gabriele Pfitzer ,&nbsp;Vladimir T. Todorov ,&nbsp;René Mantke ,&nbsp;Thomas Enzmann ,&nbsp;Hendrik Borgmann ,&nbsp;Olaf Grisk","doi":"10.1016/j.vph.2025.107515","DOIUrl":"10.1016/j.vph.2025.107515","url":null,"abstract":"<div><h3>Objective</h3><div>This study tested if arterial reactivity to soluble guanylate cyclase (sGC)/protein kinase G (PKG) pathway activation depends on age, vessel localization as well as diameter and investigated the molecular mechanisms involved in sGC activator-induced vasodilation in human arteries.</div></div><div><h3>Methods</h3><div>sGC/PKG were stimulated by sodium nitroprusside (SNP) or the sGC activator cinaciguat. Mesenteric and intrarenal arteries from young and aged mice as well as from patients who underwent elective colon resection or nephrectomy were investigated by wire myography. Phosphorylation of the regulatory 20-kDa light-chain of myosin at serine 19 (MLC₂₀-S19) and targeting-subunit-of-myosin-phosphatase at threonine 853 and serine 668 (MYPT1-T853 and MYPT1-S668) were determined by Western blot.</div></div><div><h3>Results</h3><div>In murine vessels, SNP- and cinaciguat-induced vasodilation was significantly less in intrarenal than in mesenteric arteries and not age-dependent. Human intrarenal and mesenteric arteries showed a similar vasodilation in response to SNP and cinaciguat. In both vascular beds arteries with a lumen diameter &lt; 700 μm showed a stronger cinaciguat-induced vasodilation than arteries with a lumen diameter &gt; 700 μm. Cinaciguat (0.1 μmol/l) increased PKG-dependent MYPT1-S668 phosphorylation in &lt;700 μm vessels but not in &gt;700 μm vessels. Cinaciguat significantly reduced MLC₂₀-S19 phosphorylation only in &lt;700 μm mesenteric arteries.</div></div><div><h3>Conclusions</h3><div>In contrast to murine arteries, SNP- and cinaciguat-induced vasodilation is similar in human intrarenal and mesenteric arteries. In the human vasculature, small diameter arteries are more responsive to sGC activation than large diameter vessels irrespective of the degree of MLC₂₀-S19 phosphorylation.</div></div>","PeriodicalId":23949,"journal":{"name":"Vascular pharmacology","volume":"160 ","pages":"Article 107515"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}