Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Discovery of the Low-Hemorrhagic Antithrombotic Effect of Montelukast by Targeting FXIa in Mice.","authors":"Yang Zhou, Dong Wang, Juhong Wu, Yingying Qi, Meiru Song, Huiqiao Yao, Christopher Kai Liao, Haili Lin, Meijuan Huang, Dexiang Zhuo, Longguang Jiang, Cai Yuan, Yuanzhong Chen, Mingdong Huang, Jinyu Li, Peng Xu","doi":"10.1161/ATVBAHA.124.322145","DOIUrl":"10.1161/ATVBAHA.124.322145","url":null,"abstract":"<p><strong>Background: </strong>FXIa (coagulation factor XIa) is considered as a promising antithrombotic target with reduced hemorrhagic liabilities. The objective of this study was to identify a small-molecule inhibitor of FXIa as a potential low-hemorrhagic anticoagulant.</p><p><strong>Methods: </strong>A high-throughput virtual screening was conducted using a drug repurposing library with the catalytic domain of FXIa as the bait. The identified inhibitor's anticoagulant activity was evaluated in vitro and in both arterial and venous murine thrombotic models. The dependency of the inhibitor on FXIa was further examined using FXI^-/- mice. Hemorrhagic risks were subsequently evaluated in models of both localized and major bleeding.</p><p><strong>Results: </strong>Virtual screening led to the identification of montelukast, a commonly used antiasthmatic drug, as a potent and specific FXIa inhibitor (half maximal inhibitory concentration of 0.17 μmol/L). MK exhibited anticoagulant effects comparable to those of 2 mostly prescribed anticoagulants (warfarin and apixaban) in both arterial and venous thrombotic models. Notably, in stark contrast to the pronounced hemorrhagic risks of warfarin and apixaban, MK did not measurably increase the tendency of localized or major bleeding. Furthermore, MK did not prolong the time to arterial thrombotic occlusion in FXI^-/- mice, while effectively inhibited arterial occlusion induced by the reinfusion of recombinant FXIa, confirming that MK's anticoagulant activity is mediated by plasma FXIa. Additionally, MK ameliorated inflammation levels and mitigated pulmonary microthrombus formation in a septic mouse model. Moreover, combination therapy with MK enhanced the antithrombotic effects of antiplatelets without an obvious increase of hemorrhage.</p><p><strong>Conclusions: </strong>This proof-of-concept study suggests the potent low-hemorrhage antithrombotic effect of MK by targeting FXIa and unveiling a new therapeutic application of MK.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e150-e162"},"PeriodicalIF":7.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ECM Modifications Driven by Age and Metabolic Stress Directly Promote Vascular Smooth Muscle Cell Osteogenic Processes.","authors":"Meredith Whitehead, Maria Faleeva, Rafael Oexner, Susan Cox, Lukas Schmidt, Manuel Mayr, Catherine M Shanahan","doi":"10.1161/ATVBAHA.124.321467","DOIUrl":"10.1161/ATVBAHA.124.321467","url":null,"abstract":"<p><strong>Background: </strong>The ECM (extracellular matrix) provides the microenvironmental niche sensed by resident vascular smooth muscle cells (VSMCs). Aging and disease are associated with dramatic changes in ECM composition and properties; however, their impact on VSMC phenotype remains poorly studied.</p><p><strong>Methods: </strong>Here, we describe a novel in vitro model system that utilizes endogenous ECM to study how modifications associated with age and metabolic disease impact VSMC phenotype. ECM was synthesized using primary human VSMCs and modified during culture or after decellularization. Integrity, stiffness, and composition of the ECM was measured using superresolution microscopy, atomic force microscopy, and proteomics, respectively. VSMCs reseeded onto the modified ECM were analyzed for viability and osteogenic differentiation.</p><p><strong>Results: </strong>ECMs produced in response to mineral stress showed extracellular vesicle-mediated hydroxyapatite deposition and sequential changes in collagen composition and ECM properties. VSMCs seeded onto the calcified ECM exhibited increased extracellular vesicle release and Runx2 (Runt-related transcription factor 2)-mediated osteogenic gene expression due to the uptake of hydroxyapatite, which led to increased reactive oxygen species and the induction of DNA damage signaling. VSMCs seeded onto the nonmineralized, senescent ECM also exhibited increased Runx2-mediated osteogenic gene expression and accelerated calcification. In contrast, glycated ECM specifically induced increased ALP (alkaline phosphatase) activity, and this was dependent on RAGE (receptor for advanced glycation end products) signaling with both ALP and RAGE receptor inhibition attenuating calcification.</p><p><strong>Conclusions: </strong>ECM modifications associated with aging and metabolic disease can directly induce osteogenic differentiation of VSMCs via distinct mechanisms and without the need for additional stimuli. This highlights the importance of the ECM microenvironment as a key driver of phenotypic modulation acting to accelerate age-associated vascular pathologies and provides a novel model system to study the mechanisms of calcification.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"424-442"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11856005/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142999205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Sex Differences in Cardiovascular-Kidney-Metabolic Syndrome: 30-Year US Trends and Mortality Risks-Brief Report.","authors":"","doi":"10.1161/ATV.0000000000000183","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000183","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 3","pages":"e100"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut Microbiota Alterations in Patients With Kawasaki Disease.","authors":"Prasant K Jena, Moshe Arditi, Magali Noval Rivas","doi":"10.1161/ATVBAHA.124.321201","DOIUrl":"10.1161/ATVBAHA.124.321201","url":null,"abstract":"<p><p>The intestinal microbiota influences many host biological processes, including metabolism, intestinal barrier functions, and immune responses in the gut and distant organs. Alterations in its composition have been associated with the development of inflammatory disorders and cardiovascular diseases, including Kawasaki disease (KD). KD is an acute pediatric vasculitis of unknown etiology and the leading cause of acquired heart disease in children in the United States. The presence of gastrointestinal symptoms in the acute phase of KD has been associated with an increased risk of treatment resistance and the development of coronary artery aneurysms. Studies report alterations in fecal bacterial communities of patients with KD, characterized by the blooming of pathogenic bacteria and decreased relative abundance of short-chain fatty acid-producing bacteria. However, causality and functionality cannot be established from these observational patient cohorts of KD. This highlights the need for more advanced and rigorous studies to establish causality and functionality in both experimental models of KD vasculitis and patient cohorts. Here, we review the evidence linking an altered gut microbiota composition to the development of KD, assess the potential mechanisms involved in this process, and discuss the potential therapeutic value of these observations.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"345-358"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11998981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High Glucose Treatment Induces Nuclei Aggregation of Microvascular Endothelial Cells via the <i>foxo1a</i>-<i>klf2a</i> Pathway.","authors":"Xiaoning Wang, Xinyi Kang, Bowen Li, Changsheng Chen, Liping Chen, Dong Liu","doi":"10.1161/ATVBAHA.124.321719","DOIUrl":"10.1161/ATVBAHA.124.321719","url":null,"abstract":"<p><strong>Background: </strong>Hyperglycemia is a major contributor to endothelial dysfunction and blood vessel damage, leading to severe diabetic microvascular complications. Despite the growing body of research on the underlying mechanisms of endothelial cell (EC) dysfunction, the available drugs based on current knowledge fall short of effectively alleviating these complications. Therefore, our endeavor to explore novel insights into the cellular and molecular mechanisms of endothelial dysfunction is crucial for the field.</p><p><strong>Methods: </strong>In this study, we performed a high-resolution imaging and time-lapse imaging analysis of the behavior of ECs in <i>Tg(kdrl:ras-mCherry::fli1a:nGFP</i>) zebrafish embryos upon high glucose treatment. Genetic manipulation and chemical biology approaches were utilized to analyze the underlying mechanism of high glucose-induced nuclei aggregation and aberrant migration of zebrafish ECs and cultured human ECs. Bioinformatical analysis of single-cell RNA-sequencing data and molecular biological techniques was performed to identify the target genes of <i>foxo1a</i>.</p><p><strong>Results: </strong>In this study, we observed that the high glucose treatment resulted in nuclei aggregation of ECs in zebrafish intersegmental vessels. Additionally, the aberrant migration of microvascular ECs in high glucose-treated embryos, which might be a cause of nuclei aggregation, was discovered. High glucose induced aggregation of vascular endothelial nuclei via <i>foxo1a</i> downregulation in zebrafish embryos. Then, we revealed that high glucose resulted in the downregulation of <i>foxo1a</i> expression and increased the expression of its direct downstream effector, <i>klf2a</i>, through which the aberrant migration and aggregation of vascular endothelial nuclei were caused.</p><p><strong>Conclusions: </strong>High glucose treatment caused the nuclei of ECs to aggregate in vivo, which resembles the crowded nuclei of ECs in microaneurysms. High glucose suppresses <i>foxo1a</i> expression and increases the expression of its downstream effector, <i>klf2a</i>, thereby causing the aberrant migration and aggregation of vascular endothelial nuclei. Our findings provide a novel insight into the mechanism of microvascular complications in hyperglycemia.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"398-411"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11856006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monocyte-Derived cxcl12 Guides a Directional Migration of Blood Vessels in Zebrafish.","authors":"Xiaofeng Lu, Xiaoning Wang, Bowen Li, Xin Wang, Xuchu Duan, Dong Liu","doi":"10.1161/ATVBAHA.124.321588","DOIUrl":"10.1161/ATVBAHA.124.321588","url":null,"abstract":"<p><strong>Background: </strong>Sprouting blood vessels, reaching the aimed location, and establishing the proper connections are vital for building vascular networks. Such biological processes are subject to precise molecular regulation. So far, the mechanistic insights into understanding how blood vessels grow to the correct position are limited. In particular, the guide cues and the signaling-originating cells remain elusive.</p><p><strong>Methods: </strong>Live imaging analysis was used to observe the vascular developmental process of zebrafish. Whole-mount in situ hybridization and fluorescent in situ hybridization were used to detect the expression profiles of the genes. Single-cell sequencing analysis was conducted to identify the guiding protein and its originating cells.</p><p><strong>Results: </strong>Taking advantage of live imaging analysis, we described a directional blood vessel migration in the vascularization process of zebrafish pectoral fins. We demonstrated that pectoral fin vessel c migrated over long distances and was anastomosed with the second pair of intersegmental vessels. Furthermore, we found the cxcl12a-cxcr4a axis specifically guided this long-distance extension of pectoral fin vessel c-intersegmental vessel, and either inhibition or overexpression of cxcl12a-cxcr4a signaling both mislead the growth of pectoral fin vessel c to ectopic areas. Finally, based on an analysis of single-cell sequencing data, we revealed that a population of monocytes expresses the Cxcl12a, which guides the migration of the vascular sprout.</p><p><strong>Conclusions: </strong>Our study identified Cxcl12a as the signaling molecule for orchestrating the organotypic-specific long-distance migration and anastomosis of the pectoral fin vessel and the intersegmental vessels in zebrafish. We discovered a specific cluster of <i>gata1</i> (globin transcription factor 1)-positive monocytes responsible for expressing Cxcl12a. The findings offer novel insights into the mechanisms underlying organotypic vascularization in vertebrates.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"386-397"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11855996/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Effect of Vectors on Human Endothelial Cell Signal Transduction: Implications for Cardiovascular Gene Therapy.","authors":"","doi":"10.1161/ATV.0000000000000181","DOIUrl":"https://doi.org/10.1161/ATV.0000000000000181","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"45 3","pages":"e99"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143514218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cardiovascular Disease and Cancer: A Dangerous Liaison.","authors":"Alexandra A C Newman, Jessie M Dalman, Kathryn J Moore","doi":"10.1161/ATVBAHA.124.319863","DOIUrl":"10.1161/ATVBAHA.124.319863","url":null,"abstract":"<p><p>The field of cardio-oncology has traditionally focused on the impact of cancer and its therapies on cardiovascular health. Mounting clinical and preclinical evidence, however, indicates that the reverse may also be true: cardiovascular disease can itself influence tumor growth and metastasis. Numerous epidemiological studies have reported that individuals with prevalent cardiovascular disease have an increased incidence of cancer. In parallel, studies using preclinical mouse models of myocardial infarction, heart failure, and cardiac remodeling support the notion that cardiovascular disorders accelerate the growth of solid tumors and metastases. These findings have ushered in a new and burgeoning field termed reverse cardio-oncology that investigates the impact of cardiovascular disease pathophysiology on cancer emergence and progression. Recent studies have begun to illuminate the mechanisms driving this relationship, including shared risk factors, reprogramming of immune responses, changes in gene expression, and the release of cardiac factors that result in selective advantages for tumor cells or their local milieu, thus exacerbating cancer pathology. Here, we review the evidence supporting the relationship between cardiovascular disease and cancer, the mechanistic pathways enabling this connection, and the implications of these findings for patient care.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"359-371"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11864891/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142943409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"XOR-Derived ROS in Tie2-Lineage Cells Including Endothelial Cells Promotes Aortic Aneurysm Progression in Marfan Syndrome.","authors":"Hiroki Yagi, Hiroshi Akazawa, Qing Liu, Kimiko Yamamoto, Kan Nawata, Akiko Saga-Kamo, Masahiko Umei, Hiroshi Kadowaki, Ryo Matsuoka, Akito Shindo, Shun Okamura, Haruhiro Toko, Norifumi Takeda, Masahiko Ando, Haruo Yamauchi, Norihiko Takeda, Mehdi A Fini, Minoru Ono, Issei Komuro","doi":"10.1161/ATVBAHA.124.321527","DOIUrl":"10.1161/ATVBAHA.124.321527","url":null,"abstract":"<p><strong>Background: </strong>Marfan syndrome (MFS) is an inherited disorder caused by mutations in the <i>FBN1</i> gene encoding fibrillin-1, a matrix component of extracellular microfibrils. The main cause of morbidity and mortality in MFS is thoracic aortic aneurysm and dissection, but the underlying mechanisms remain undetermined.</p><p><strong>Methods: </strong>To elucidate the role of endothelial XOR (xanthine oxidoreductase)-derived reactive oxygen species in aortic aneurysm progression, we inhibited in vivo function of XOR either by endothelial cell (EC)-specific disruption of the <i>Xdh</i> gene or by systemic administration of an XOR inhibitor febuxostat in MFS mice harboring the <i>Fbn1</i> missense mutation p.(Cys1041Gly). We assessed the aberrant activation of mechanosensitive signaling in the ascending aorta of <i>Fbn1</i>^C1041G/+ mice. Further analysis of human aortic ECs investigated the mechanisms by which mechanical stress upregulates XOR expression.</p><p><strong>Results: </strong>We found a significant increase in reactive oxygen species generation in the ascending aorta of patients with MFS and <i>Fbn1</i>^C1041G/+ mice, which was associated with a significant increase in protein expression and enzymatic activity of XOR protein in aortic ECs. Genetic disruption of <i>Xdh</i> in ECs or treatment with febuxostat significantly suppressed aortic aneurysm progression and improved perivascular infiltration of macrophages. Mechanistically, mechanosensitive signaling involving FAK (focal adhesion kinase)-p38 MAPK (p38 mitogen-activated protein kinase) and Egr-1 (early growth response-1) was aberrantly activated in the ascending aorta of <i>Fbn1</i>^C1041G/+ mice, and mechanical stress on human aortic ECs upregulated XOR expression through Egr-1 upregulation. Consistently, EC-specific knockout of XOR or systemic administration of febuxostat in <i>Fbn1</i>^C1041G/+ mice suppressed reactive oxygen species generation, FAK-p38 MAPK activation, and Egr-1 upregulation.</p><p><strong>Conclusions: </strong>Aberrant activation of mechanosensitive signaling in vascular ECs triggered endothelial XOR activation and reactive oxygen species generation, which contributes to the progression of aortic aneurysms in MFS. These findings highlight a drug repositioning approach using a uric acid-lowering drug febuxostat as a potential therapy for MFS.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e63-e77"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelium Modulates the Prothrombotic Phenotype of Factor V Leiden: Evidence From an Ex Vivo Model.","authors":"Nadine Schwarz, Jens Müller, Hannah L McRae, Sara Reda, Behnaz Pezeshkpoor, Johannes Oldenburg, Bernd Pötzsch, Heiko Rühl","doi":"10.1161/ATVBAHA.124.322116","DOIUrl":"10.1161/ATVBAHA.124.322116","url":null,"abstract":"<p><strong>Background: </strong>Clinical expressivity of the thrombophilic factor V Leiden (FVL) mutation is highly variable. Recently, we demonstrated an increased APC (activated protein C) response in asymptomatic FVL carriers compared with FVL carriers with a history of venous thromboembolism (VTE) after in vivo coagulation activation. Here, we further explored this association using a recently developed ex vivo model based on patient-specific endothelial colony-forming cells (ECFCs).</p><p><strong>Methods: </strong>ECFCs and citrated plasma were obtained from FVL carriers with previous VTE (VTE+, n=9), FVL carriers without previous VTE (VTE-, n=8), and 7 healthy controls. Coagulation was activated by TF (tissue factor) in defibrinated recalcified plasma added to confluent cell cultures. Thrombin and APC concentration were measured over time, and the respective areas under the curve (AUCs) were calculated. Additionally, inhibition kinetics of exogenously added APC, APC inhibitor levels, and APC sensitivity ratios were measured in plasma. Expression of TM (thrombomodulin) and EPCR (endothelial protein C receptor) on ECFCs was assessed using cell-based ELISAs.</p><p><strong>Results: </strong>In autologous plasma on ECFCs, the APC response (AUC APC/AUC thrombin) was higher in FVL VTE- than in FVL VTE+ patients (0.138 versus 0.028; <i>P</i>=0.026). APC inhibitor levels, APC inactivation kinetics, and APC sensitivity ratios did not differ between cohorts. Crossover experiments, which combined pooled plasma from FVL VTE- patients with FVL VTE+ ECFCs in the ex vivo model, and vice versa, showed increased APC response rates when FVL VTE- ECFCs were used, regardless of the plasma component. In cell-based ELISAs, TM and EPCR expression showed no significant difference.</p><p><strong>Conclusions: </strong>Although the FVL gene product induces an almost identical APC resistance phenotype in plasma, the endothelial cell-dependent APC response rates differ significantly, with a higher APC response in asymptomatic FVL carriers. Further studies are warranted to elucidate the disease-modulating role of the endothelium in FVL carriers at the molecular level.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"412-423"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143021649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}