Circulation research最新文献

{"title":"Habitual Exercise Modulates Neuroimmune Interaction to Mitigate Aortic Stiffness.","authors":"Jae Min Cho,Khoa Vu,Seul-Ki Park,Enbo Zhu,Yan-Ruide Li,Peng Zhao,Tomohiro Yokota,Lili Yang,Rong Lu,Yang Kevin Xiang,Ying H Shen,Mark W Chapleau,Tzung K Hsiai","doi":"10.1161/circresaha.124.325656","DOIUrl":"https://doi.org/10.1161/circresaha.124.325656","url":null,"abstract":"BACKGROUNDExercise augments hemodynamic shear to activate mechano-sensitive molecular transducers in the vascular endothelium. Recently, the central nervous system has been reported to mediate neuroimmune interaction in the aortic adventitia (AA). Whether exercise modulates the sympathetic nerve interaction with the immune cells to mitigate aortic stiffness remains unknown.METHODS AND RESULTSFour weeks of Ang II (angiotensin II) infusion to C57BL/6 mice increased neural activation to increase the expression of TH (tyrosine hydroxylase) for sympathetic nerve axons and norepinephrine levels along with the colocalization of synapsin and β2-AR (β2-adrenergic receptor)-positive macrophages in the AA. This Ang II-mediated sympathetic nerve and macrophage interaction activated fibroblasts to increase vascular fibrosis and arterial pulse wave velocity. Sympathetic denervation with celiac ganglionectomy or 6-hydroxydopamine treatment abrogated Ang II-mediated TH+, AA thickness, and pulse wave velocity. Single-cell RNA sequencing analyses of the AA revealed that Ang II increased the circulating monocyte-derived macrophages (Ccr2+CD80) but reduced the resident macrophages (Lyve1+CD163). Gene ontology analysis of differentially expressed genes unveiled that voluntary wheel running mitigated Ang II-mediated increase in Ccr2+CD80 macrophages, cytokine-mediated signaling pathways in macrophages, and extracellular matrix deposition in fibroblasts. Macrophage depletion with Ki20227 (colony stimulating factor 1 receptor inhibitor) reduced Ang II-mediated synapsin+ macrophages. Using the Ccr2 knock-in (Ccr2gfp)/knock-out (Ccr2KO) mice, we observed that Ang II-mediated increases in Ccr2+ macrophages were expressed in Ccr2gfp mice but were absent in Ccr2KO mice. Also, Ang II-induced increases in synapsin expression, neighboring Ccr2+ cells, AA thickness, and pulse wave velocity were reduced in Ccr2KO mice. Both Ki20227 and Ccr2KO reduced the Ang II-mediated increase in TH levels. Furthermore, voluntary wheel running-mediated reduction in vascular fibrosis and aortic stiffness were mitigated by a β2-AR agonist, terbutaline, indicating β2-AR in neuroimmune modulation.CONCLUSIONSExercise mitigates Ang II-mediated sympathetic axon interaction with the circulating monocyte-derived macrophages in the AA to attenuate vascular fibrosis and aortic stiffness.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"15 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893211","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":"Overload of Neprilysin in Placental Extracellular Vesicles Disrupts CNP-NPRB-Mediated Communication Between Vascular Endothelial and Smooth Muscle Cells: A Trigger for Symptoms of Preeclampsia.","authors":"Chengjin He,Yi Du,Ruixin Chen,Yuhan Qiu,Jiayu Huang,Li Lin,Mark D Kilby,Yong Fu,Hongbo Qi,Philip N Baker,Chao Tong","doi":"10.1161/circresaha.124.325673","DOIUrl":"https://doi.org/10.1161/circresaha.124.325673","url":null,"abstract":"BACKGROUNDPreeclampsia is a placenta-origin pregnancy complication. Although its development has long been divided into 2 stages: abnormal placentation (stage I) and the release of factors from the hypoperfused placenta into circulation, triggering preeclampsia due to endothelial dysfunction (stage II), the placenta-derived substances coupling the 2 stages remain unclear.METHODSExtracellular vesicles (EVs) from normal and preeclampsia-complicated placentas were intravenously administered to pregnant mice, and blood pressure was recorded throughout pregnancy. The differential cargo, including NEP (neprilysin), of placental EVs in normal and preeclamptic placentas was identified by LC-MS, and the cell types involved in NEP expression in the placenta were determined by single-cell RNA sequencing. The effects of placental EVs and recombinant mouse NEP on the uterine arteries were assessed by myography. Placenta-specific NEP overexpression mice were established by in situ injection of adenovirus. The binding affinity between NEP and the vasodilative peptides was determined using an Octet instrument. NEP-overexpressing HUVECs were established to measure CNP (C-type natriuretic peptide) release and cocultured with NPRB (natriuretic peptide receptor-B) knockdown vascular smooth muscle cells (VSMCs) to measure cGMP production in VSMCs.RESULTSPlacental EVs from preeclamptic pregnancies impaired vascular endothelium-dependent vasodilation and induced preeclampsia in mice. NEP was expressed predominantly by syncytiotrophoblasts and upregulated in placental EVs from preeclamptic pregnancies. Recombinant mouse NEP administration resulted in outcomes like those of administration of placental EVs from preeclamptic pregnancies. Placenta-specific NEP overexpression disturbed maternal hemodynamics, resulting in hypertension and proteinuria of the mice. CNP exhibited high binding affinity for NEP, and NEP upregulation in HUVECs inhibited CNP release, which further influenced the production of cGMP in VSMCs; however, this effect was largely blunted in NPRB-deficient VSMCs.CONCLUSIONSExcessive NEP in placental EVs from preeclamptic pregnancies is transported into the endothelial cells of uterine and placental arteries to cleave and degrade CNP, resulting in compromised CNP paracrine activity and NPRB-mediated cGMP production in adjacent VSMCs and triggering the hypertensive manifestation of preeclampsia.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"273 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143893210","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":"Endothelial KLF15/VASN Axis Inhibits Angiogenesis via Activation of Notch1 Signaling.","authors":"Jia Zhang,Jia-Jia Zhao,Han-Dan Zhou,Jing Chen,Mo-Na Hong,Ji-Guang Wang,Ping-Jin Gao,Xiao-Dong Li","doi":"10.1161/circresaha.124.325494","DOIUrl":"https://doi.org/10.1161/circresaha.124.325494","url":null,"abstract":"BACKGROUNDAngiogenesis is a dynamic process fine-tuned by transcription factors in endothelial cells. The KLF15 (Krüppel-like factor 15)-mediated transcriptional regulation mechanism is critical for cardiovascular diseases. However, the role of KLF15 in governing angiogenesis remains unknown.METHODSKLF15 and VASN (vasorin) were deleted from endothelial cells using tamoxifen-inducible Cdh5 promoter-driven Cre recombinase in EC-KLF15 knockout (KO) and EC-VASN KO mice, respectively. EC-KLF15 KO, EC-VASN KO, and control mice were subjected to retinal angiogenesis or tumor cell transplantation. The RNA sequencing, assay for transposase-accessible chromatin using sequencing, and chromatin immunoprecipitation sequencing were conducted to identify VASN as a downstream effector of KLF15. Cell proliferation, wound healing, tube formation, and sprouting assays were performed to delineate endothelial cell function.RESULTSIn EC-KLF15 KO mice and adenovirus-mediated KLF15 overexpression mice, we showed that KLF15 negatively regulated retinal angiogenesis, as confirmed in cultured endothelial cells. KLF15 opened chromatin, bound to the promoters of GC-rich sequences, and transactivated the expression of VASN. Subsequently, VASN suppressed endothelial angiogenic function, which was essential for Dll4 (delta-like ligand 4)-induced Notch1 signaling activation. Moreover, increased expression of VASN in EC-KLF15 KO mice suppressed retinal angiogenesis, which was attenuated by γ-secretase inhibitor. EC-VASN KO mice recapitulated the promotion of retinal angiogenesis in EC-KLF15 KO mice. Finally, the EGF (epidermal growth factor)-like domain of VASN was essential for its interaction with Notch1, and VASN EGF-like domain-derived peptides activated Notch1 signaling and suppressed angiogenesis.CONCLUSIONSThe KLF15/VASN axis negatively regulates angiogenesis by activating Notch1 signaling. KLF15 and VASN might represent novel therapeutic targets for the treatment of impaired angiogenesis-related diseases and tumors.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"69 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889334","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":"Natural Killer T Cells Link Stress Hyperglycemia to Cognitive Decline in HFpEF.","authors":"Pasquale Mone,Michele Ciccarelli,Stanislovas S Jankauskas,Francesca Picone,Germano Guerra,Gianluca Testa,Francesco Moccia,Roberto Magliuolo,Marco Di Mauro,Antonio De Luca,Albino Carrizzo,Carmine Vecchione,Gaetano Santulli","doi":"10.1161/circresaha.125.326315","DOIUrl":"https://doi.org/10.1161/circresaha.125.326315","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"10 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143885493","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":"Stellate Ganglia: A Key Therapeutic Target for Malignant Ventricular Arrhythmia in Heart Disease.","authors":"Yu-Long Li,Yu Li,Huiyin Tu,Anthony J Evans,Tapan A Patel,Hong Zheng,Kaushik P Patel","doi":"10.1161/circresaha.124.325384","DOIUrl":"https://doi.org/10.1161/circresaha.124.325384","url":null,"abstract":"Malignant ventricular arrhythmias (VAs), such as ventricular tachycardia and ventricular fibrillation, are the cause of approximately half a million deaths per year in the United States, which is a common lethal event in heart disease, such as hypertension, catecholaminergic polymorphic ventricular tachycardia, takotsubo cardiomyopathy, long-QT syndrome, and progressing into advanced heart failure. A common characteristic of these heart diseases, and the subsequent development of VAs, is the overactivation of the sympathetic nervous system. Current treatments for VAs in these heart diseases, such as β-adrenergic receptor blockers and cardiac sympathetic ablation, aim at inhibiting cardiac sympathetic overactivation. However, these treatments do not translate into becoming efficacious as long-term suppressors of ventricular tachycardia/ventricular fibrillation events. As a key regulatory component in the heart, cardiac postganglionic sympathetic neurons residing in the stellate ganglia (SGs) release neurotransmitters (such as norepinephrine and NPY [neuropeptide Y]) to perform their regulatory role in dictating cardiac function. Growing evidence from animal experiments and clinical studies has demonstrated that the remodeling of the SG may be intimately involved in malignant arrhythmogenesis. This identifies the SG as a key potential therapeutic target for the treatment of malignant VAs in heart disease. Therefore, this review summarizes the role of SG in ventricular arrhythmogenesis and updates the novel targeting of SG for clinical treatment of VAs in heart disease.","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"8 1","pages":"1049-1069"},"PeriodicalIF":20.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876427","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":"Thyroid Hormone Signaling in Cerebrovascular Malformations: A Regulator of Vascular Stability and Repair.","authors":"Seokhyun Kim,Minho Shong,Injune Kim","doi":"10.1161/circresaha.125.326460","DOIUrl":"https://doi.org/10.1161/circresaha.125.326460","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"17 1","pages":"1028-1030"},"PeriodicalIF":20.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876400","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":"MAIT Cells in Lipoprotein Metabolism: A New Pathway for VLDL Clearance?","authors":"Majid M Syed-Abdul,Gary F Lewis","doi":"10.1161/circresaha.125.326462","DOIUrl":"https://doi.org/10.1161/circresaha.125.326462","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"6 1","pages":"982-984"},"PeriodicalIF":20.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876411","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":"Novel Humanized Aortic Valve Calcification Model.","authors":"Dunpeng Cai,Lindsey Saint,John Markley,Shi-You Chen","doi":"10.1161/circresaha.124.325976","DOIUrl":"https://doi.org/10.1161/circresaha.124.325976","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"24 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871996","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":"Impact of Cholesterol on Cardiac Mitochondrial Function.","authors":"Gary D Lopaschuk","doi":"10.1161/circresaha.125.326464","DOIUrl":"https://doi.org/10.1161/circresaha.125.326464","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"41 1","pages":"943-945"},"PeriodicalIF":20.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143876401","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":"Tracking Endothelial Extracellular Vesicles in a Mouse Model of Atherosclerosis.","authors":"Mandy Kunze Guo,Corey A Scipione,Leandro C D Breda,Kamalben Prajapati,Sneha Raju,Steven R Botts,Majed Abdul-Samad,Sarvatit Patel,Garry Yu,Andrew C Dudley,Jason E Fish,Kathryn L Howe","doi":"10.1161/circresaha.124.326024","DOIUrl":"https://doi.org/10.1161/circresaha.124.326024","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":"68 1","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866635","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}