Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Hidden Power: PAR4's Role in Liver Damage From Acetaminophen Overdose in Mice.","authors":"NaShea C Kendrick, Marvin T Nieman","doi":"10.1161/ATVBAHA.124.321881","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321881","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613766","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":"Emerging Imaging Techniques for Atherosclerosis in Systemic Immune-Mediated Inflammatory Conditions.","authors":"George Markousis-Mavrogenis, Muzzamal Habib, Daniel M Huck, Florian Andre, Henning Steen, Monica Mukherjee, Sophie I Mavrogeni, Brittany Weber","doi":"10.1161/ATVBAHA.124.321202","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321202","url":null,"abstract":"<p><p>Atherosclerosis affects patients with systemic immune-mediated inflammatory diseases at an increased rate compared with the general population. In recent years, our understanding of the pathophysiology of atherosclerosis has advanced considerably. Nevertheless, cardiovascular imaging modalities that can adequately assess the biological background of atherosclerosis have not reached widespread clinical adoption. Novel developments in cardiac imaging have the potential to enhance the diagnostic yield of these modalities further while providing essential insights into the anatomy, composition, and biology of atherosclerotic lesions. In this review, we highlight some of the latest developments in the field for the evaluation of atherosclerosis using advances in echocardiography, computed tomography, positron emission tomography, and cardiovascular magnetic resonance. Additionally, we discuss evidence specifically in patients with immune-mediated inflammatory diseases and outline unmet research needs for future development.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613762","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":"VEGFC Overexpression in Kidney Progenitor Cells Is a Model of Renal Lymphangiectasia.","authors":"Michael D Donnan, Dilip K Deb, Vidhi Dalal, Valentin David, Daniele Procissi, Susan E Quaggin","doi":"10.1161/ATVBAHA.124.319743","DOIUrl":"10.1161/ATVBAHA.124.319743","url":null,"abstract":"<p><strong>Background: </strong>Lymphangiogenesis is believed to be a protective response in the setting of multiple forms of kidney injury and mitigates the progression of interstitial fibrosis. To augment this protective response, promoting kidney lymphangiogenesis is being investigated as a potential treatment to slow the progression of kidney disease. As injury-related lymphangiogenesis is driven by signaling from the receptor VEGFR3 (vascular endothelial growth factor receptor 3) in response to the cognate growth factor VEGF (vascular endothelial growth factor)-C released by tubular epithelial cells, this signaling pathway is a candidate for future kidney therapeutics. However, the consequences to kidney development and function to targeting this signaling pathway remain poorly defined.</p><p><strong>Methods: </strong>We generated a new mouse model expressing <i>Vegfc</i> under regulation of the nephron progenitor Six2Cre driver strain (<i>Six2Vegfc</i>). Mice underwent a detailed phenotypic evaluation. Whole kidneys were processed for histology and 3-dimensional imaging.</p><p><strong>Results: </strong><i>Six2Vegfc</i> mice had reduced body weight and kidney function compared with littermate controls. <i>Six2Vegfc</i> kidneys demonstrated large peripelvic fluid-filled lesions with distortion of the pelvicalcyceal system which progressed in severity with age. Three-dimensional imaging showed a 3-fold increase in total cortical vascular density. Histology confirmed a substantial increase in LYVE1+ (lymphatic vessel endothelial hyaluronan receptor-1)/PDPN+ (podoplanin)/VEGFR3+ lymphatic capillaries extending alongside EMCN+ (endomucin) peritubular capillaries. There was no change in EMCN+ peritubular capillary density.</p><p><strong>Conclusions: </strong>Kidney lymphatic density was robustly increased in the <i>Six2Vegfc</i> mice. There were no changes in peritubular blood capillary density despite these endothelial cells also expressing VEGFR3. The model resulted in malformation of the lymphatic hilar plexus, resulting in severe hydronephrosis that resembled a human condition termed renal lymphangiectasia. This study defines the vascular consequences of augmenting VEGFC signaling during kidney development and provides new insight into human renal lymphatic malformations.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142613771","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":"m⁶A Modification of Profilin-1 in Vascular Smooth Muscle Cells Drives Phenotype Switching and Neointimal Hyperplasia via Activation of the p-ANXA2/STAT3 Pathway.","authors":"Xiao-Fei Gao, Ai-Qun Chen, Hao-Yue Tang, Xiang-Quan Kong, Huan Zhang, Zhi-Mei Wang, Wei Lu, Li-Guo Wang, Feng Wang, Wen-Ying Zhou, Yue Gu, Guang-Feng Zuo, Zhen Ge, Jun-Jie Zhang, Shao-Liang Chen","doi":"10.1161/ATVBAHA.124.321399","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321399","url":null,"abstract":"<p><strong>Background: </strong>In-stent restenosis is characterized by a significant reduction in lumen diameter within the stented segment, primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMCs) and neointimal hyperplasia. PFN1 (profilin-1), an actin-sequestering protein extensively studied in amyotrophic lateral sclerosis, remains less explored in neointimal hyperplasia.</p><p><strong>Methods: </strong>Utilizing single-cell RNA sequencing alongside data from in-stent restenosis patients and various experimental in-stent restenosis models (swine, rats, and mice), we investigated the role of PFN1 in promoting VSMC phenotype switching and neointimal hyperplasia.</p><p><strong>Results: </strong>Single-cell RNA sequencing of stenotic rat carotid arteries revealed a critical role for PFN1 in neointimal hyperplasia, a finding corroborated in stented swine coronary arteries, in-stent restenosis patients, PFN1^SMC-IKO (SMC-specific PFN1 knockout) mice, and PFN1 overexpressed mice. PFN1 deletion was shown to suppress VSMC phenotype switching and neointimal hyperplasia in PFN1^SMC-IKO mice subjected to a wire-injured model. To elucidate the observed discordance in PFN1 mRNA and protein levels, we identified that METTL3 (N⁶-methyladenosine methyltransferase) and YTHDF3 (N⁶-methyladenosine-specific reader) enhance PFN1 translation efficiency in an N⁶-methyladenosine-dependent manner, confirmed through experiments involving METTL3 knockout and YTHDF3 knockout mice. Furthermore, PFN1 was mechanistically found to interact with the phosphorylation of ANXA2 (annexin A2) by recruiting Src, promoting the phosphorylation of STAT3, a typical transcription factor known to induce VSMC phenotype switching.</p><p><strong>Conclusions: </strong>This study unveils the significance of PFN1 N⁶-methyladenosine modification in VSMCs, demonstrating its role in promoting phenotype switching and neointimal hyperplasia through the activation of the p-ANXA2 (phospho-ANXA2)/STAT3 pathway.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589781","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":"ApoE Receptor-2 R952Q Variant in Macrophages Elevates Soluble LRP1 to Potentiate Hyperlipidemia and Accelerate Atherosclerosis in Mice.","authors":"Vanessa Turkson, April Haller, Anja Jaeschke, David Y Hui","doi":"10.1161/ATVBAHA.124.321748","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321748","url":null,"abstract":"<p><strong>Background: </strong>apoER2 (apolipoprotein E receptor-2) is a transmembrane receptor in the low-density lipoprotein receptor (LDLR) family with unique tissue expression. A single-nucleotide polymorphism that encodes the R952Q sequence variant has been associated with elevated plasma cholesterol levels and increased myocardial infarction risk in humans. The objective of this study was to delineate the mechanism underlying the association between the apoER2 R952Q variant and increased atherosclerosis risk.</p><p><strong>Methods: </strong>An apoER2 R952Q mouse model was generated using a CRISPR/Cas9 strategy, intercrossed with LDLR knockout mice, followed by feeding a Western-type high-fat high-cholesterol diet for 16 weeks. Atherosclerosis was investigated by immunohistology. Plasma lipids and lipid distributions among the various lipoprotein classes were analyzed by colorimetric assay. Tissue-specific effects of the R952Q sequence variant on atherosclerosis were analyzed by bone marrow transplant studies. sLRP1 (soluble low-density lipoprotein receptor-related protein 1) was measured in plasma and conditioned media from bone marrow-derived macrophages by ELISA and GST-RAP (glutathione S-transferase-receptor-associated protein) pull-down, respectively. P38 MAPK (mitogen-activated protein kinase) phosphorylation in VLDL (very-low-density lipoprotein)-treated macrophages was determined by Western blot analysis.</p><p><strong>Results: </strong>Consistent with observations in humans with this sequence variant, the apoER2 R952Q mutation exacerbated diet-induced hypercholesterolemia, via impediment of plasma triglyceride-rich lipoprotein clearance, to accelerate atherosclerosis in Western diet-fed LDLR knockout mice. Reciprocal bone marrow transplant experiments revealed that the apoER2 R952Q mutation in bone marrow-derived cells instead of non-bone marrow-derived cells was responsible for the increase in hypercholesterolemia and atherosclerosis. Additional data showed that the apoER2 R952Q mutation in macrophages promotes VLDL-induced LRP1 (low-density lipoprotein receptor-related protein 1) shedding in a p38 MAPK-dependent manner.</p><p><strong>Conclusions: </strong>The apoER2 R952Q mouse model recapitulates characteristics observed in human disease. The underlying mechanism is that the apoER2 R952Q mutation in macrophages exacerbates VLDL-stimulated sLRP1 production in a p38 MAPK-dependent manner, resulting in its competition with cell surface LRP1 to impede triglyceride-rich lipoprotein clearance, thereby resulting in increased hypercholesterolemia and accelerated atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589768","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":"Cure of Congenital Purpura Fulminans via Expression of Engineered Protein C Through Neonatal Genome Editing in Mice.","authors":"Tomoki Togashi, Nemekhbayar Baatartsogt, Yasumitsu Nagao, Yuji Kashiwakura, Morisada Hayakawa, Takafumi Hiramoto, Takayuki Fujiwara, Eriko Morishita, Osamu Nureki, Tsukasa Ohmori","doi":"10.1161/ATVBAHA.123.319460","DOIUrl":"https://doi.org/10.1161/ATVBAHA.123.319460","url":null,"abstract":"<p><strong>Background: </strong>PC (protein C) is a plasma anticoagulant encoded by <i>PROC</i>; mutation in both <i>PROC</i> alleles results in neonatal purpura fulminans-a fatal systemic thrombotic disorder. In the present study, we aimed to develop a genome editing treatment to cure congenital PC deficiency.</p><p><strong>Methods: </strong>We generated an engineered APC (activated PC) to insert a furin-cleaving peptide sequence between light and heavy chains. The engineered PC was expressed in the liver of mice using an adeno-associated virus vector or CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated 9)-mediated genome editing using an adeno-associated virus vector in vivo.</p><p><strong>Results: </strong>The engineered PC could be released in its activated form and significantly prolonged the plasma coagulation time independent of the cofactor activity of PS (protein S) in vitro. The adeno-associated virus vector-mediated expression of the engineered PC, but not wild-type PC, prolonged coagulation time owing to the inhibition of activated coagulation FV (factor V) in a dose-dependent manner and abolished pathological thrombus formation in vivo in C57BL/6J mice. The insertion of <i>EGFP</i> sequence conjugated with self-cleaving peptide sequence at <i>Alb</i> locus via neonatal in vivo genome editing using adeno-associated virus vector resulted in the expression of EGFP in 7% of liver cells, mainly via homology-directed repair, in mice. Finally, we succeeded in improving the survival of PC-deficient mice by expressing the engineered PC via neonatal genome editing in vivo.</p><p><strong>Conclusions: </strong>These results suggest that the expression of engineered PC via neonatal genome editing is a potential cure for severe congenital PC deficiency.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589776","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":"Trem2/Tyrobp Signaling Protects Against Aortic Dissection and Rupture by Inhibiting Macrophage Activation in Mice.","authors":"Zenghui Zhang, Maoxiong Wu, Lei Yao, Weibin Zhou, Xiao Liu, Zhiteng Chen, Ping Hua, Leibo Xu, Lei Lv, Chiyu Liu, Chunling Huang, Sixu Chen, Zhaoqi Huang, Yuna Huang, Jiaqi He, Tingfeng Chen, Jingfeng Wang, Woliang Yuan, Zhaoyu Liu, Yangxin Chen","doi":"10.1161/ATVBAHA.124.321429","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.321429","url":null,"abstract":"<p><strong>Background: </strong>The development of aortic dissection (AD) is closely associated with inflammation. The Trem2 (triggering receptor expressed on myeloid cells 2)/Tyrobp (TYRO protein tyrosine kinase-binding protein) signaling pathway critically regulates innate immunity and has emerged as an important target in cardiovascular diseases; however, its role in AD remains unclear.</p><p><strong>Methods: </strong>Transcriptome data from human and mouse ADs were used to perform differentially expressed gene-based protein-protein interaction network analyses. <i>Tyrobp</i> knockout (Tyrobp^-/-), myeloid cell-specific <i>Tyrobp</i>^-/- (Tyrobp^fl/fl Lyz2^cre), and <i>Trem2</i> knockout (Trem2^-/^-) mice were given β-aminopropionitrile monofumarate in drinking water to induce AD. To dissect the role of macrophages in <i>Tyrobp</i> deficiency-mediated AD progression, macrophages were depleted using clodronate liposomes. Bulk and single-cell RNA sequencing, immunofluorescence staining, and quantitative real-time polymerase chain reaction were performed to assess inflammation and the underlying mechanisms of Tyrobp in AD.</p><p><strong>Results: </strong>Network analysis identified <i>Tyrobp</i> as a hub gene of AD, with elevated levels observed in both human and mouse ADs. Global deletion and myeloid cell-specific deficiency of <i>Tyrobp</i> in mice significantly increased AD incidence and exacerbated extracellular matrix degradation and macrophage infiltration within the aortic wall. Macrophage depletion mitigated the adverse effects of <i>Tyrobp</i> deficiency on AD progression. Additionally, <i>Tyrobp</i> deficiency enhanced TLR (Toll-like receptor)-4 signaling and macrophage activation, which were abrogated by TLR4 inhibitors. Furthermore, deletion of the Tyrobp-associated receptor <i>Trem2</i> significantly aggravated mouse AD development, whereas Trem2 agonist treatment conferred protection against AD.</p><p><strong>Conclusions: </strong>Our findings suggest a novel role for the Trem2/Tyrobp axis in AD development in mice. Enhancement of Trem2/Tyrobp signaling may represent a promising strategy for the prevention and treatment of AD. Future studies to clarify the role of Trem2/Tyrobp in human AD are warranted.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142589787","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":"COVID-19 Is a Coronary Artery Disease Risk Equivalent and Exhibits a Genetic Interaction With ABO Blood Type.","authors":"James R Hilser, Neal J Spencer, Kimia Afshari, Frank D Gilliland, Howard Hu, Arjun Deb, Aldons J Lusis, WH Wilson Tang, Jaana A Hartiala, Stanley L Hazen, Hooman Allayee","doi":"10.1161/ATVBAHA.124.321001","DOIUrl":"10.1161/ATVBAHA.124.321001","url":null,"abstract":"<p><strong>Background: </strong>COVID-19 is associated with acute risk of major adverse cardiac events (MACE), including myocardial infarction, stroke, and mortality (all-cause). However, the duration and underlying determinants of heightened risk of cardiovascular disease and MACE post-COVID-19 are not known.</p><p><strong>Methods: </strong>Data from the UK Biobank was used to identify COVID-19 cases (n=10 005) who were positive for polymerase chain reaction (PCR⁺)-based tests for SARS-CoV-2 infection (n=8062) or received hospital-based <i>International Classification of Diseases version-10 (ICD-10</i>) codes for COVID-19 (n=1943) between February 1, 2020 and December 31, 2020. Population controls (n=217 730) and propensity score-matched controls (n=38 860) were also drawn from the UK Biobank during the same period. Proportional hazard models were used to evaluate COVID-19 for association with long-term (>1000 days) risk of MACE and as a coronary artery disease risk equivalent. Additional analyses examined whether COVID-19 interacted with genetic determinants to affect the risk of MACE and its components.</p><p><strong>Results: </strong>The risk of MACE was elevated in COVID-19 cases at all levels of severity (HR, 2.09 [95% CI, 1.94-2.25]; <i>P</i><0.0005) and to a greater extent in cases hospitalized for COVID-19 (HR, 3.85 [95% CI, 3.51-4.24]; <i>P</i><0.0005). Hospitalization for COVID-19 represented a coronary artery disease risk equivalent since incident MACE risk among cases without history of cardiovascular disease was even higher than that observed in patients with cardiovascular disease without COVID-19 (HR, 1.21 [95% CI, 1.08-1.37]; <i>P</i><0.005). A significant genetic interaction was observed between the <i>ABO</i> locus and hospitalization for COVID-19 (<i>P</i>_interaction=0.01), with risk of thrombotic events being increased in subjects with non-O blood types (HR, 1.65 [95% CI, 1.29-2.09]; <i>P</i>=4.8×10^-5) to a greater extent than subjects with blood type O (HR, 0.96 [95% CI, 0.66-1.39]; <i>P</i>=0.82).</p><p><strong>Conclusions: </strong>Hospitalization for COVID-19 represents a coronary artery disease risk equivalent, with post-acute myocardial infarction and stroke risk particularly heightened in non-O blood types. These results may have important clinical implications and represent, to our knowledge, one of the first examples of a gene-pathogen exposure interaction for thrombotic events.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2321-2333"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387526","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":"GP VI-Mediated Platelet Activation and Procoagulant Activity Aggravate Inflammation and Aortic Wall Remodeling in Abdominal Aortic Aneurysm.","authors":"Tobias Feige, Agnes Bosbach, Kim J Krott, Joscha Mulorz, Madhumita Chatterjee, Julia Ortscheid, Evelyn Krüger, Irena Krüger, Niloofar Salehzadeh, Silvia Goebel, Wiebke Ibing, Maria Grandoch, Götz Münch, Markus U Wagenhäuser, Hubert Schelzig, Margitta Elvers","doi":"10.1161/ATVBAHA.123.320615","DOIUrl":"10.1161/ATVBAHA.123.320615","url":null,"abstract":"<p><strong>Background: </strong>Platelets play an important role in cardiovascular and cerebrovascular diseases. Abdominal aortic aneurysm (AAA) is a highly lethal, atherosclerosis-related disease with characteristic features of progressive dilatation of the abdominal aorta and degradation of the vessel wall, accompanied by chronic inflammation. Platelet activation and procoagulant activity play a decisive role in the AAA pathology as they might trigger AAA development in both mice and humans.</p><p><strong>Methods: </strong>The present study investigated the impact of the major platelet collagen receptor GP (platelet glycoprotein) VI in pathophysiological processes underlying AAA initiation and progression. For experimental AAA induction in mice, PPE (porcine pancreatic elastase) and the external PPE model were used.</p><p><strong>Results: </strong>Genetic deletion of GP VI offered protection of mice against aortic diameter expansion in experimental AAA. Mechanistically, GP VI deficiency resulted in decreased inflammation with reduced infiltration of neutrophils and platelets into the aortic wall. Furthermore, remodeling of the aortic wall was improved in the absence of GP VI, as indicated by reduced MMP (matrix metalloproteinase)-2/9 and OPN (osteopontin) plasma levels and an enhanced α-SMA (α-smooth muscle actin) content within the aortic wall, accompanied by reduced cell apoptosis. Consequently, an elevation in intima/media thickness and elastin content was observed in GP VI-deficient PPE mice, resulting in a significantly reduced aortic diameter expansion and reduced aneurysm incidence. In patients with AAA, enhanced plasma levels of soluble GP VI and fibrin, as well as fibrin accumulation within the intraluminal thrombus might serve as new biomarkers to detect AAA early. Moreover, we hypothesize that GP VI might play a role in procoagulant activity and thrombus stabilization via binding to fibrin.</p><p><strong>Conclusions: </strong>In conclusion, our results emphasize the potential need for a GP VI-targeted antiplatelet therapy to reduce AAA initiation and progression, as well as to protect patients with AAA from aortic rupture.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2294-2317"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142103905","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":"Decoding Macrophage Heterogeneity to Unravel Vascular Inflammation as a Path to Precision Medicine.","authors":"Sarvesh Chelvanambi, Julius L Decano, Holger Winkels, Chiara Giannarelli, Masanori Aikawa","doi":"10.1161/ATVBAHA.124.319571","DOIUrl":"https://doi.org/10.1161/ATVBAHA.124.319571","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"44 11","pages":"2253-2257"},"PeriodicalIF":7.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493715","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}