{"title":"m<sup>6</sup>A 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":"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<sup>SMC-IKO</sup> (SMC-specific PFN1 knockout) mice, and PFN1 overexpressed mice. PFN1 deletion was shown to suppress VSMC phenotype switching and neointimal hyperplasia in PFN1<sup>SMC-IKO</sup> mice subjected to a wire-injured model. To elucidate the observed discordance in PFN1 mRNA and protein levels, we identified that METTL3 (N<sup>6</sup>-methyladenosine methyltransferase) and YTHDF3 (YTH N6-methyladenosine RNA binding protein F3; N<sup>6</sup>-methyladenosine-specific reader) enhance PFN1 translation efficiency in an N<sup>6</sup>-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 (SRC proto-oncogene, nonreceptor tyrosine kinase), promoting the phosphorylation of STAT3 (signal transducer and activator of transcription 3), a typical transcription factor known to induce VSMC phenotype switching.</p><p><strong>Conclusions: </strong>This study unveils the significance of PFN1 N<sup>6</sup>-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":"2543-2559"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11593993/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Novel Therapeutics and Upcoming Clinical Trials Targeting Inflammation in Cardiovascular Diseases.","authors":"Nicola Potere, Aldo Bonaventura, Antonio Abbate","doi":"10.1161/ATVBAHA.124.319980","DOIUrl":"10.1161/ATVBAHA.124.319980","url":null,"abstract":"<p><p>Cardiovascular disease (CVD) remains a major health burden despite significant therapeutic advances accomplished over the last decades. It is widely and increasingly recognized that systemic inflammation not only represents a major cardiovascular risk and prognostic factor but also plays key pathogenic roles in CVD development and progression. Despite compelling preclinical evidence suggesting large potential of anti-inflammatory pharmacological interventions across numerous CVDs, clinical translation remains incomplete, mainly due to (1) yet undefined molecular signaling; (2) challenges of safety and efficacy profile of anti-inflammatory drugs; and (3) difficulties in identifying optimal patient candidates and responders to anti-inflammatory therapeutics, as well as optimal therapeutic windows. Randomized controlled trials demonstrated the safety/efficacy of canakinumab and colchicine in secondary cardiovascular prevention, providing confirmation for the involvement of a specific inflammatory pathway (NLRP3 [NACHT, LRR, and PYD domain-containing protein 3] inflammasome/IL [interleukin]-1β) in atherosclerotic CVD. Colchicine was recently approved by the US Food and Drug Administration for this indication. Diverse anti-inflammatory drugs targeting distinct inflammatory pathways are widely used for the management of other CVDs including myocarditis and pericarditis. Ongoing research efforts are directed to implementing anti-inflammatory therapeutic strategies across a growing number of CVDs, through repurposing of available anti-inflammatory drugs and development of novel anti-inflammatory compounds, which are herein concisely discussed. This review also summarizes the main characteristics and findings of completed and upcoming randomized controlled trials directly targeting inflammation in CVDs, and discusses major challenges and future perspectives in the exciting and constantly expanding landscape of cardioimmunology.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2371-2395"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142387528","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":"Tuning Into Immune Cell Responses of Chronic Stress With Intravital Microscopy.","authors":"Matthias Nahrendorf","doi":"10.1161/ATVBAHA.124.321865","DOIUrl":"10.1161/ATVBAHA.124.321865","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2507-2508"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493713","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":"Adding a New Piece to the ASGR1 Puzzle: ANGPTL3.","authors":"Itsaso Garcia-Arcos","doi":"10.1161/ATVBAHA.124.321882","DOIUrl":"10.1161/ATVBAHA.124.321882","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2450-2452"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11630090/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543370","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":"Immune-Mediated Inflammatory Diseases, Dyslipidemia, and Cardiovascular Risk: A Complex Interplay.","authors":"Michael J Wilkinson, Michael D Shapiro","doi":"10.1161/ATVBAHA.124.319983","DOIUrl":"10.1161/ATVBAHA.124.319983","url":null,"abstract":"<p><p>Individuals with autoimmune inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, are at increased risk for cardiovascular disease. While these diseases share common features of systemic inflammation, the impact of individual autoimmune inflammatory conditions on circulating lipids and lipoproteins varies by specific disease, disease activity, and the immune-suppressing medications used to treat these conditions. A common feature observed in many autoimmune inflammatory diseases is the development of a proatherogenic dyslipidemic state, characterized by dysfunctional HDLs (high-density lipoproteins) and increased oxidation of LDLs (low-density lipoproteins). Various disease-modifying antirheumatic drugs also have complex and variable effects on lipids, and it is critical to take this into consideration when evaluating lipid-related risk in individuals with immune-mediated inflammatory conditions. This review aims to critically evaluate the current understanding of the relationship between immune-mediated inflammatory diseases and dyslipidemia, the underlying mechanisms contributing to atherogenesis, and the impact of various pharmacotherapies on lipid profiles and cardiovascular risk. We also discuss the role of lipid-lowering therapies, particularly statins, in managing residual risk in this high-risk population and explore the potential of emerging therapies with complementary anti-inflammatory and lipid-lowering effects.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2396-2406"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11602385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543372","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}
Carlotta Onnis, Renu Virmani, Anna Madra, Valentina Nardi, Rodrigo Salgado, Roberta Montisci, Riccardo Cau, Alberto Boi, Amir Lerman, Carlo N De Cecco, Peter Libby, Luca Saba
{"title":"Whys and Wherefores of Coronary Arterial Positive Remodeling.","authors":"Carlotta Onnis, Renu Virmani, Anna Madra, Valentina Nardi, Rodrigo Salgado, Roberta Montisci, Riccardo Cau, Alberto Boi, Amir Lerman, Carlo N De Cecco, Peter Libby, Luca Saba","doi":"10.1161/ATVBAHA.124.321504","DOIUrl":"10.1161/ATVBAHA.124.321504","url":null,"abstract":"<p><p>Positive remodeling (PR) is an atherosclerotic plaque feature defined as an increase in arterial caliber at the level of an atheroma, in response to increasing plaque burden. The mechanisms that lead to its formation are incompletely understood, but its role in coronary atherosclerosis has major clinical implications. Indeed, plaques with PR have elevated risk of provoking acute cardiac events. Hence, PR figures among the high-risk plaque features that cardiac imaging studies should report. This review aims to provide an overview of the current literature on coronary PR. It outlines the pathophysiology of PR, the different techniques used to assess its presence, and the imaging findings associated to PR, on both noninvasive and invasive studies. This review also summarizes clinical observations, trials, and studies, focused on the impact of PR on clinical outcome.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2416-2427"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11594009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142543373","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}
Jihui Lee, Megan E Goeckel, Allison Levitas, Sarah Colijn, Jimann Shin, Anna Hindes, Geonyoung Mun, Zarek Burton, Bharadwaj Chintalapati, Ying Yin, Javier Abello, Lilianna Solnica-Krezel, Amber N Stratman
{"title":"CXCR3-CXCL11 Signaling Restricts Angiogenesis and Promotes Pericyte Recruitment.","authors":"Jihui Lee, Megan E Goeckel, Allison Levitas, Sarah Colijn, Jimann Shin, Anna Hindes, Geonyoung Mun, Zarek Burton, Bharadwaj Chintalapati, Ying Yin, Javier Abello, Lilianna Solnica-Krezel, Amber N Stratman","doi":"10.1161/ATVBAHA.124.321434","DOIUrl":"10.1161/ATVBAHA.124.321434","url":null,"abstract":"<p><strong>Background: </strong>Endothelial cell (EC)-pericyte interactions are known to remodel in response to hemodynamic forces; yet there is a lack of mechanistic understanding of the signaling pathways that underlie these events. Here, we have identified a novel signaling network regulated by blood flow in ECs-the chemokine receptor CXCR3 (CXC motif chemokine receptor 3) and one of its ligands, CXCL11 (CXC motif chemokine ligand 11)-that delimits EC angiogenic potential and promotes pericyte recruitment to ECs during development.</p><p><strong>Methods: </strong>We investigated the role of CXCR3 on vascular development using both 2- and 3-dimensional in vitro assays, to study EC-pericyte interactions and EC behavioral responses to blood flow. Additionally, genetic mutants and pharmacological modulators were used in zebrafish in vivo to study the impacts of CXCR3 loss and gain of function on vascular development.</p><p><strong>Results: </strong>In vitro modeling of EC-pericyte interactions demonstrates that suppression of EC-specific CXCR3 signaling leads to loss of pericyte association with EC tubes. In vivo, phenotypic defects are particularly noted in the cranial vasculature, where we see a loss of pericyte association with ECs and expansion of the vasculature in zebrafish treated with the Cxcr3 inhibitor AMG487 or in homozygous <i>cxcr3.1/3.2/3.3</i> triple mutants. We also demonstrate that CXCR3-deficient ECs are more elongated, move more slowly, and have impaired EC-EC junctions compared with their control counterparts.</p><p><strong>Conclusions: </strong>Our results suggest that CXCR3 signaling in ECs helps promote vascular stabilization events during development by preventing EC overgrowth and promoting pericyte recruitment.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2577-2595"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11594002/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364167","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":"Elucidating VEGF Biology: A Journey of Discovery and Clinical Translation.","authors":"Tommaso Mori, Naresh Kumar R N, Napoleone Ferrara","doi":"10.1161/ATVBAHA.124.319574","DOIUrl":"10.1161/ATVBAHA.124.319574","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":"44 12","pages":"2361-2365"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11606529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142738150","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}
Safwat T Khan, Neha Ahuja, Sonia Taïb, Shabana Vohra, Ondine Cleaver, Sara S Nunes
{"title":"Single-Cell Meta-Analysis Uncovers the Pancreatic Endothelial Cell Transcriptomic Signature and Reveals a Key Role for NKX2-3 in PLVAP Expression.","authors":"Safwat T Khan, Neha Ahuja, Sonia Taïb, Shabana Vohra, Ondine Cleaver, Sara S Nunes","doi":"10.1161/ATVBAHA.124.321781","DOIUrl":"10.1161/ATVBAHA.124.321781","url":null,"abstract":"<p><strong>Background: </strong>The pancreatic vasculature displays tissue-specific physiological and functional adaptations that support rapid insulin response by β-cells. However, the digestive enzymes have made it difficult to characterize pancreatic endothelial cells (ECs), resulting in the poor understanding of pancreatic EC specialization.</p><p><strong>Methods: </strong>Available single-nuclei/single-cell RNA-sequencing data sets were mined to identify pancreatic EC-enriched signature genes and to develop an integrated atlas of human pancreatic ECs. We validated the findings using independent single-nuclei/single-cell RNA-sequencing data, bulk RNA-sequencing data of isolated ECs, spatial transcriptomics data, immunofluorescence, and RNAScope of selected markers. The NK2 homeobox 3 (NKX2-3) TF (transcription factor) was expressed in HUVECs via gene transfection, and the expression of pancreatic EC-enriched signature genes was assessed via RT-qPCR.</p><p><strong>Results: </strong>We defined a pancreatic EC-enriched gene signature conserved across species and developmental stages that included genes involved in ECM (extracellular matrix) composition (COL15A1 and COL4A1), permeability and barrier function (PLVAP, EHD4, CAVIN3, HSPG2, ROBO4, HEG1, and CLEC14A), and key signaling pathways (S1P [sphingosine-1-phosphate], TGF-β [transforming growth factor-β], RHO/RAC GTPase [guanosine triphosphatase], PI3K/AKT [phosphoinositide 3-kinase/protein kinase B], and PDGF [platelet-derived growth factor]). The integrated atlas revealed the vascular hierarchy within the pancreas. We identified and validated a specialized islet capillary subpopulation characterized by genes involved in permeability (PLVAP and EHD4), immune-modulation (FABP5, HLA-C, and B2M), ECM composition (SPARC and SPARCL1), IGF (insulin-like growth factor) signaling (IGFBP7), and membrane transport (SLCO2A1, SLC2A3, and CD320). Importantly, we identified NKX2-3 as a key TF enriched in pancreatic ECs. DNA-binding motif analysis found NKX2-3 motifs in ≈40% of the signature genes. Induction of NKX2-3 in HUVECs promoted the expression of the islet capillary EC-enriched genes PLVAP and SPARCL1.</p><p><strong>Conclusions: </strong>We defined a validated transcriptomic signature of pancreatic ECs and uncovered their intratissue transcriptomic heterogeneity. We showed that NKX2-3 acts upstream of PLVAP and provided a single-cell online resource that can be further explored by the community: https://vasconcelos.shinyapps.io/pancreatic_endothelial/.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2596-2615"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11594071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493711","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":"A Sophisticated Model of Human Atherosclerosis on a Chip.","authors":"Brandon J Tefft","doi":"10.1161/ATVBAHA.124.321804","DOIUrl":"10.1161/ATVBAHA.124.321804","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"2473-2475"},"PeriodicalIF":7.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142493708","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}