Circulation research最新文献

{"title":"LncRNA MIR181A1HG Deficiency Attenuates Vascular Inflammation and Atherosclerosis.","authors":"Huaner Ni, Yulong Ge, Ying Zhuge, Xiaoqiang Liu, Hangwei Chen, Junyi Liu, Weifeng Li, Xiang Wang, Gu Shen, Qiuling Wang, Rulin Zhuang, Mark W Feinberg, Fang Wang","doi":"10.1161/CIRCRESAHA.124.325196","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325196","url":null,"abstract":"<p><strong>Background: </strong>Endothelial cell (EC) dysfunction and vascular inflammation are critical in the initiation and progression of atherosclerosis. Long noncoding RNAs play a critical role in vascular pathology, but relatively little is known about their involvement in controlling vascular inflammation. MIR181A1HG is a conserved long noncoding RNA located in juxtaposition with miR-181a1 and miR-181b1, both involved in vascular inflammation. The study aims to investigate the role of MIR181A1HG in regulating vascular inflammation.</p><p><strong>Methods: </strong>We examined the expression of MIR181A1HG in both human and mouse atherosclerotic lesions. Loss-of-function and gain-of-function studies, and multiple RNA-protein interaction assays were used to investigate the role and molecular mechanisms of MIR181A1HG in vascular inflammation and atherosclerosis. The atherosclerotic phenotypes of MIR181A1HG^-/-ApoE^-/- mice were analyzed in combination with single-cell RNA sequencing. The transcriptional regulation of MIR181A1HG was verified through luciferase reporter and chromatin immunoprecipitation assays.</p><p><strong>Results: </strong>MIR181A1HG expression was abundant in ECs and significantly increased in both human and mouse atherosclerotic lesions. MIR181A1HG^-/-ApoE^-/- mice had reduced NLRP (NLR family pyrin domain containing) 3 inflammasome signaling, EC activation, monocyte infiltration, and atherosclerotic lesion formation. Genetic deletion of MIR181A1HG in myeloid sells did not alter the progression of atherosclerosis. Single-cell RNA sequencing analysis revealed that MIR181A1HG deficiency reduced the proportion of immune cells and enriched anti-inflammation pathways in EC clusters in atherosclerotic lesions. In contrast, EC-specific MIR181A1HG overexpression promoted NLRP3 inflammasome signaling, EC activation, and atherosclerotic lesion formation, effects that were reversed by pharmacological inhibition of NLRP3 (MCC950). MIR181A1HG was transcriptionally activated via an NF-κB (nuclear factor kappa B)/p65-dependent pathway. Mechanistically, MIR181A1HG mediated these effects on regulating NLRP3 inflammasome and EC activation in part through decoying Foxp1 (forkhead box transcription factor 1) away from the promoters of target genes, which was independent of the miR-181a1/b1 cluster. Finally, EC-specific Foxp1 silencing reversed the antiatherosclerotic effect mediated by MIR181A1HG-deletion in vivo.</p><p><strong>Conclusions: </strong>These findings identify MIR181A1HG as a central driver of vascular inflammation in atherosclerosis by its ability to decoy Foxp1 away from target gene promoters and activate NLRP3 inflammasome in the vascular endothelium. Our study suggests MIR181A1HG as a future therapeutic target for vascular inflammatory disease states.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143566287","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":"NR4A1 Acts as a Novel Regulator of Platelet Activation and Thrombus Formation.","authors":"Wenhua Liu, Gaoxiang Li, Jianfeng Shi, Yu Gao, Peiliang Fang, Yichao Zhao, Fangyuan Zhong, Xiao Guo, Yuyan Lyu, Xingwen Da, Zhaoyan Li, Jingjing Fa, Liuhua Hu, Ancai Yuan, Lei Chen, Junling Liu, Alex F Chen, Bin Sheng, Yong Ji, Xiyuan Lu, Jun Pu","doi":"10.1161/CIRCRESAHA.124.325645","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325645","url":null,"abstract":"<p><strong>Background: </strong>Mounting evidence indicates that nuclear receptors play a critical regulatory role in platelet pathophysiology and thrombotic disorders. Although NR4A (the nuclear receptor subfamily 4 group A) plays an important role in cardiovascular pathophysiology, the expression profile and biological function of NR4A member 1 (NR4A1) in platelets have never been reported.</p><p><strong>Methods: </strong>We evaluated the functions and the underlying mechanisms of NR4A1 in platelet activation and thrombus formation using platelet-specific NR4A1-deficient mice and NR4A1-specific agonists. Using a hyperlipidemic mouse model and platelets from patients with hypercholesterolemia, we explored the influence of hypercholesterolemia on NR4A1 expression and the effects of NR4A1-specific agonists on platelet hyperreactivity induced by hypercholesterolemia.</p><p><strong>Results: </strong>NR4A1 was expressed in both human and mouse platelets. Platelet-specific NR4A1 deletion accelerated FeCl₃-induced carotid arterial occlusive thrombus formation, enhanced collagen/epinephrine-induced pulmonary thromboembolism, and exacerbated microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. NR4A1-deficient platelets exhibited enhanced agonist-induced aggregation responses, integrin α_IIbβ₃ activation, dense granule release, α-granule release, platelet spreading, and clot retraction. Consistently, pharmacological activation of NR4A1 by specific agonists decreased platelet activation in both mouse and human platelets. Mechanistically, CAP1 (adenylyl cyclase-associated protein 1) was identified as the direct downstream interacting protein of NR4A1. NR4A1 deletion decreased cAMP levels and phosphorylation of VASP (vasodilator-stimulated phosphoprotein), while NR4A1-specific agonists increased cAMP levels and phosphorylation of VASP in platelets. Importantly, NR4A1 expression in platelets was upregulated in the setting of hypercholesterolemia, which was derived from its upregulation in megakaryocytes in a reactive oxygen species-dependent manner. Platelets from hypercholesterolemic patients and mice exhibited hyperreactivity. However, NR4A1-specific agonists significantly inhibited the activation of hypercholesterolemic platelets to the levels of healthy control platelets.</p><p><strong>Conclusions: </strong>We provide the first evidence that nuclear receptor NR4A1 negatively regulates platelet activation and thrombus formation. NR4A1 may serve as a novel therapeutic target for managing thrombosis-based cardiovascular diseases, especially with hypercholesterolemia.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540372","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":"GOLM1 Promotes Atherogenesis by Activating Macrophage EGFR-ERK Signaling Cascade.","authors":"Xiaochen Gai, Fangming Liu, Yixin Chen, Baohui Zhang, Yinliang Zhang, Yuting Wu, Shuhui Yang, Linlin Chen, Weiwei Deng, Yuan Wang, Shuiyun Wang, Cuntao Yu, Jie Du, Zhengyi Zhang, Jing Wang, Hongbing Zhang","doi":"10.1161/CIRCRESAHA.124.325880","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325880","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is a chronic inflammatory disease. GOLM1 (Golgi membrane protein 1) is an inflammation-responsive protein and a mediator in some inflammation-associated pathological processes. Because we found a positive correlation between GOLM1 expression and atherosclerosis progression by checking the gene expression data set of human atherosclerotic lesions, we explored the potential significance of GOLM1 in atherosclerosis in this study.</p><p><strong>Methods: </strong>GOLM1 levels in serums and lesions of patients with atherosclerosis and mice with atherosclerosis were examined by immunostaining and ELISA. Gain-of-function and loss-of-function approaches were used to study the impacts of GOLM1 in inflammation and atherogenesis of <i>Apoe</i>^-/- mice on a Western diet. The effects of GOLM1 on macrophage behaviors were determined by OxLDL (oxidized low-density lipoprotein) uptake assay, single-cell sequencing analysis, global phosphoproteomics analysis, and molecular biological techniques. The therapeutic potential of GOLM1 neutralization for atherosclerosis was evaluated in <i>Apoe</i>^-/- mice.</p><p><strong>Results: </strong>GOLM1 was elevated in serums and lesions of patients with atherosclerosis and mice with atherosclerosis. Global deletion of GOLM1 ameliorated mouse inflammation and atherosclerosis, while knock-in of GOLM1 exacerbated these pathological manifestations. Furthermore, hepatic GOLM1 deletion reduced circulating GOLM1 and attenuated atherogenesis. Mechanistically, the expression and secretion of GOLM1 were induced in multiple mouse tissues by atherogenic stimulus, leading to the elevation of extracellular GOLM1. Extracellular GOLM1 then stimulated ERK (extracellular signal-regulated kinase) signaling cascade by binding to its putative receptor EGFR (epidermal growth factor receptor) to promote macrophage uptake of LDL (low-density lipoprotein) and enhance the corresponding macrophage immune response. Moreover, neutralizing GOLM1 by an antibody suppressed mouse inflammation and atherogenesis.</p><p><strong>Conclusions: </strong>GOLM1 is an atherogenic mediator and a promising therapeutic target for the intervention of atherosclerotic diseases.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536511","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":"Intestinal Microbiota Contributes to the Development of Cardiovascular Inflammation and Vasculitis in Mice.","authors":"Prasant K Jena, Daiko Wakita, Angela C Gomez, Thacyana T Carvalho, Asli E Atici, Emily Aubuchon, Meena Narayanan, Youngho Lee, Michael C Fishbein, Yoshihiro Takasato, Yosuke Kurashima, Hiroshi Kiyono, Patrice D Cani, Willem M de Vos, David M Underhill, Suzanne Devkota, Shuang Chen, Kenichi Shimada, Timothy R Crother, Moshe Arditi, Magali Noval Rivas","doi":"10.1161/CIRCRESAHA.124.325079","DOIUrl":"10.1161/CIRCRESAHA.124.325079","url":null,"abstract":"<p><strong>Background: </strong>Alterations in the intestinal microbiota contribute to the pathogenesis of various cardiovascular disorders, but how they affect the development of Kawasaki disease, an acute pediatric vasculitis, remains unclear. Here, using a murine model mimicking Kawasaki disease vasculitis, we assessed the contribution of the intestinal microbiota to the development of vascular inflammation.</p><p><strong>Methods and results: </strong>We report that depleting the gut microbiota reduces the development of cardiovascular inflammation in a murine model mimicking Kawasaki disease vasculitis. The development of cardiovascular lesions was associated with alterations in the intestinal microbiota composition and, notably, a decreased abundance of <i>Akkermansia muciniphila</i> and <i>Faecalibacterium prausnitzii</i>. Oral supplementation with either of these live or pasteurized individual bacteria or with short-chain fatty acids produced by them attenuated cardiovascular inflammation, as reflected by decreased local immune cell infiltrations. Treatment with Amuc_1100, the TLR-2 signaling outer membrane protein from <i>Akkermansia muciniphila</i>, also reduced the severity of vascular inflammation.</p><p><strong>Conclusions: </strong>This study reveals an underappreciated gut microbiota-cardiovascular inflammation axis in Kawasaki disease vasculitis pathogenesis and identifies specific intestinal commensals that regulate vasculitis in mice by producing metabolites or via extracellular proteins capable of enhancing and supporting gut barrier function.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":""},"PeriodicalIF":16.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536591","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":"Roles of Sirtuins in Cardiovascular Diseases: Mechanisms and Therapeutics.","authors":"Yang-Nan Ding, Hui-Yu Wang, Xiao-Feng Chen, Xiaoqiang Tang, Hou-Zao Chen","doi":"10.1161/CIRCRESAHA.124.325440","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325440","url":null,"abstract":"<p><p>Cardiovascular diseases (CVDs) are experiencing a rapid surge and are widely recognized as the leading cause of mortality in the current aging society. Given the multifactorial etiology of CVDs, understanding the intricate molecular and cellular mechanisms is imperative. Over the past 2 decades, many scientists have focused on Sirtuins, a family of nicotinamide adenine dinucleotide-dependent deacylases. Sirtuins are highly conserved across species, from yeasts to primates, and play a crucial role in linking aging and diseases. Sirtuins participate in nearly all key physiological and pathological processes, ranging from embryogenic development to stress response and aging. Abnormal expression and activity of Sirtuins exist in many aging-related diseases, while their activation has shown efficacy in mitigating these diseases (eg, CVDs). In terms of research, this field has maintained fast, sustained growth in recent years, from fundamental studies to clinical trials. In this review, we present a comprehensive, up-to-date discussion on the biological functions of Sirtuins and their roles in regulating cardiovascular biology and CVDs. Furthermore, we highlight the latest advancements in utilizing Sirtuin-activating compounds and nicotinamide adenine dinucleotide boosters as potential pharmacological targets for preventing and treating CVDs. The key unresolved issues in the field-from the chemicobiological regulation of Sirtuins to Sirtuin-targeted CVD investigations-are also discussed. This timely review could be critical in understanding the updated knowledge of Sirtuin biology in CVDs and facilitating the clinical accessibility of Sirtuin-targeting interventions.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 5","pages":"524-550"},"PeriodicalIF":16.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522595","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":"Ischemic Conditioning Promotes Transneuronal Survival and Stroke Recovery via CD36-Mediated Efferocytosis.","authors":"Hyunwoo Ju, Il-Doo Kim, Ina Pavlova, Shang Mu, Keun Woo Park, Joseph Minkler, Ahmed Madkoor, Wei Wang, Xiaoman Wang, Zhuhao Wu, Jiwon Yang, Maria Febbraio, John W Cave, Sunghee Cho","doi":"10.1161/CIRCRESAHA.124.325428","DOIUrl":"10.1161/CIRCRESAHA.124.325428","url":null,"abstract":"<p><strong>Background: </strong>Remote ischemic conditioning (RIC) has been implicated in cross-organ protection in cerebrovascular disease, including stroke. However, the lack of a consensus protocol and controversy over the clinical therapeutic outcomes of RIC suggest an inadequate mechanistic understanding of RIC. The current study identifies RIC-induced molecular and cellular events in the blood, which enhance long-term functional recovery in experimental cerebral ischemia.</p><p><strong>Methods: </strong>Naive mice or mice subjected to transient ischemic stroke were randomly selected to receive sham conditioning or RIC in the hindlimb at 2 hours post-stroke. At 3 days post-stroke, monocyte composition in the blood was analyzed, and brain tissue was examined for monocyte-derived macrophage (Mφ), levels of efferocytosis, and CD36 expression. Mouse with a specific deletion of CD36 in monocytes/Mφs was used to establish the role of CD36 in RIC-mediated modulation of efferocytosis, transneuronal degeneration, and recovery following stroke.</p><p><strong>Results: </strong>RIC applied 2 hours after stroke increased the entry of monocytes into the injured brain. In the postischemic brain, Mφ had increased levels of CD36 expression and efferocytosis. These changes in brain Mφ were derived from RIC-induced changes in circulating monocytes. In the blood, RIC increased CD36 expression in circulating monocytes and shifted monocytes to a proinflammatory Lymphocyte antigen 6 complex (LY6C)^High state. Conditional deletion of CD36 in Mφ abrogated the RIC-induced monocyte shift in the blood and efferocytosis in the brain. During the recovery phase of stroke, RIC rescued the loss of the volume and of tyrosine hydroxylase+ neurons in substantia nigra and behavioral deficits in wild-type mice but not in mice with a specific deletion of CD36 in monocytes/Mφs.</p><p><strong>Conclusions: </strong>RIC induces a shift in monocytes to a proinflammatory state with elevated CD36 levels, and this is associated with CD36-dependent efferocytosis in Mφs that rescues delayed transneuronal degeneration in the postischemic brain and promotes stroke recovery. Together, these findings provide novel insight into our mechanistic understanding of how RIC improves poststroke recovery.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"e34-e51"},"PeriodicalIF":16.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11867857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143064064","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":"SMC Abca1 and Abcg1 Deficiency Enhances Urinary Bladder Distension but Not Atherosclerosis.","authors":"Benedek Halmos, Anouk M La Rose, Daisey Methorst, Anouk G Groenen, Dalibor Nakládal, Venetia Bazioti, Mirjam H Koster, Niels J Kloosterhuis, Azuwerus van Buiten, Elisabeth M Schouten, Nicolette C A Huijkman, Miriam Langelaar-Makkinje, Laura Bongiovanni, Simon M De Neck, Alain de Bruin, Hendrik Buikema, Leo E Deelman, Marius C van den Heuvel, Folkert Kuipers, Igle Jan de Jong, Judith C Sluimer, Helle F Jørgensen, Robert H Henning, Marit Westerterp","doi":"10.1161/CIRCRESAHA.124.325103","DOIUrl":"10.1161/CIRCRESAHA.124.325103","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Smooth muscle cells (SMCs) regulate blood flow distribution via vasoconstriction mediated by α-ARs (α-adrenergic receptors). Plasma membrane cholesterol accumulation affects α&lt;sub&gt;1&lt;/sub&gt;-AR signaling and promotes loss of SMC contractile markers in vitro. ABCA1 and ABCG1 (ATP-binding cassette transporter A1 and G1) mediate cholesterol efflux to HDL (high-density lipoprotein). ABCA1/ABCG1 show high expression in medial and low expression in intimal SMCs of atherosclerotic plaques. The role of ABCA1 and ABCG1 in SMC-mediated vasoconstriction and atherogenesis remains poorly understood.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We generated mice with SMC-specific &lt;i&gt;Abca1/Abcg1&lt;/i&gt; deficiency on the low-density lipoprotein receptor-deficient (&lt;i&gt;Ldlr&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt;&lt;sup&gt;&lt;i&gt;/&lt;/i&gt;&lt;/sup&gt;&lt;sup&gt;&lt;i&gt;-&lt;/i&gt;&lt;/sup&gt;) background by crossbreeding &lt;i&gt;Abca1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;fl/fl&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Abcg1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;fl/fl&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Ldlr&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt; mice with &lt;i&gt;Myh11Cre&lt;/i&gt;&lt;sup&gt;&lt;i&gt;ERT2&lt;/i&gt;&lt;/sup&gt; transgenic mice. To induce SMC cholesterol accumulation and atherogenesis, we fed &lt;i&gt;Myh11Cre&lt;/i&gt;&lt;sup&gt;&lt;i&gt;ERT2&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Abca1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;fl/fl&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Abcg1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;fl/fl&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Ldlr&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt;, &lt;i&gt;Myh11Cre&lt;/i&gt;&lt;sup&gt;&lt;i&gt;ERT2&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Abca1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;fl/fl&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Ldlr&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt;, &lt;i&gt;Myh11Cre&lt;/i&gt;&lt;sup&gt;&lt;i&gt;ERT2&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Abcg1&lt;/i&gt;&lt;sup&gt;&lt;i&gt;fl/fl&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Ldlr&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt;, and &lt;i&gt;Myh11Cre&lt;/i&gt;&lt;sup&gt;&lt;i&gt;ERT2&lt;/i&gt;&lt;/sup&gt;&lt;i&gt;Ldlr&lt;/i&gt;&lt;sup&gt;&lt;i&gt;-/-&lt;/i&gt;&lt;/sup&gt; mice Western-type diet for 16 weeks.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Combined &lt;i&gt;SMC-Abca1/Abcg1&lt;/i&gt; deficiency increased vasoconstriction in aortic rings induced by the α&lt;sub&gt;1&lt;/sub&gt;-AR agonist phenylephrine. Unexpectedly, &lt;i&gt;SMC-Abca1/Abcg1&lt;/i&gt; deficiency induced urinary bladder distension by &gt;20-fold. This was reversed by the α&lt;sub&gt;1&lt;/sub&gt;-AR antagonist tamsulosin, indicating its dependence on bladder neck SMC constriction. Moreover, &lt;i&gt;SMC-Abca1/Abcg1&lt;/i&gt; deficiency decreased contractile markers and increased macrophage and fibroblast markers in bladder SMCs, indicating SMC transdifferentiation. This was accompanied by free cholesterol accumulation and increased endoplasmic reticulum stress. &lt;i&gt;SMC-Abca1/Abcg1&lt;/i&gt; deficiency did not induce thoracic aorta SMC transdifferentiation, presumably due to increased cholesteryl ester accumulation and no endoplasmic reticulum stress in thoracic aorta SMCs. Surprisingly, &lt;i&gt;SMC-Abca1/Abcg1&lt;/i&gt; deficiency did not affect atherosclerotic lesion size or composition in the aortic root or brachiocephalic artery.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;We uncover a new role of SMC cholesterol efflux pathways in suppressing α&lt;sub&gt;1&lt;/sub&gt;-AR-mediated vasoconstriction and bladder SMC transdifferentiation, decreasing urinary bladder distension. Our data may provide a mechanistic link for the association between urinary bladder distension and diabetes in humans, particularly because diabetes is associated with decrease","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"491-507"},"PeriodicalIF":16.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11867804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143390297","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":"Loss of Endothelial TRPC1 Induces Aortic Hypercontractility and Hypertension.","authors":"Yifei Zhu, Yuan Chu, Yihui Lan, Sheng Wang, Yizhi Zhang, Yuan Liu, Xianfeng Wang, Fan Yu, Xin Ma","doi":"10.1161/CIRCRESAHA.124.325574","DOIUrl":"10.1161/CIRCRESAHA.124.325574","url":null,"abstract":"<p><strong>Background: </strong>The increasing prevalence of obesity-related cardiovascular diseases demands a better understanding of the contribution of different cell types to vascular function for developing new treatment strategies. Previous studies have established a fundamental role of TRPC1 (transient receptor potential channel canonical family member 1) in blood vessels. However, little is known about its functional roles within different cell types.</p><p><strong>Methods: </strong>We generated endothelial-specific TRPC1-deficient and knockin mice and analyzed their changes in vascular function under physiological and pathologically obese state. Wire myography, Ca²⁺ image, blood pressure measurements, RNA-sequencing analysis, liquid chromatography-mass spectrometry, immunoblotting, ELISA, luciferase reporter assay, and morphometric assessments were performed to unravel phenotype and molecular changes in response to the absence or presence of endothelial TRPC1.</p><p><strong>Results: </strong>Loss of endothelial TRPC1 reduced endothelial-dependent relaxation and exaggerated endothelial-dependent contraction in mouse aorta. As expected, loss of endothelial TRPC1 amplified blood pressure and decreased acetylcholine-induced intracellular Ca²⁺ concentration rise in the aorta. In endothelial-specific TRPC1-deficient mouse arteries, the mRNA profile identified upregulation of c-Fos (Fos proto-oncogene, activator protein-1 transcription factor subunit). Blockade of c-Fos rescued the impaired vasomotor tone in the aorta of mice deficient in endothelial TRPC1. Endothelial TRPC1-regulated nitric oxide/endothelin-1 production is involved in vascular c-Fos expression. Moreover, knockin of endothelial TRPC1 ameliorated enhanced endothelial-dependent contraction and hypertension in obese mice which is related to alleviated endothelial endothelin-1/c-Fos production and smooth muscle contraction.</p><p><strong>Conclusions: </strong>Our results identify endothelial TRPC1 as a previously unclear regulator of vascular changes and blood pressure in both physiological and pathologically obese state, and it is associated with nitric oxide/endothelin-1/c-Fos signaling.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":" ","pages":"508-523"},"PeriodicalIF":16.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143255009","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":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000710","DOIUrl":"https://doi.org/10.1161/RES.0000000000000710","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 5","pages":"453-454"},"PeriodicalIF":16.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522557","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":"Better Late Than Early? The Role of the Vascular Endothelium in Late-Onset Menopause.","authors":"Gurleen Kaur, Naomi M Hamburg, Emily S Lau","doi":"10.1161/CIRCRESAHA.125.326197","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.125.326197","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"136 5","pages":"470-472"},"PeriodicalIF":16.5,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522280","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}