Arteriosclerosis, Thrombosis, and Vascular Biology最新文献

{"title":"Disarming FcγRIIA: Separating Immunothrombosis From Protective Immunity.","authors":"Pierre Mangin, Elizabeth E Gardiner","doi":"10.1161/ATVBAHA.126.325504","DOIUrl":"https://doi.org/10.1161/ATVBAHA.126.325504","url":null,"abstract":"","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878836","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":"<i>Twist1</i> Promotes Endothelial Phenotypic Transition and Unstable Plaque Phenotype During Atherosclerosis.","authors":"Danielle C M Dy, Thiel Lehman, Benjamin Donald Henson, Jeeya Shah, Jessica Lin, Tiffany Riascos, Robert Wirka","doi":"10.1161/ATVBAHA.126.324428","DOIUrl":"10.1161/ATVBAHA.126.324428","url":null,"abstract":"<p><strong>Background: </strong>Comprehensive investigation of endothelial cell (EC) dysfunction during atherosclerosis with single-cell omics has resulted in the proposal that ECs undergo multiple alternative cell fate decisions during disease, but lack of lineage tracing or spatial localization complicates interpretation of these data. <i>TWIST1</i>, a causal gene for multiple atherosclerotic vascular diseases, is activated with low shear stress in ECs, and EC-<i>Twist1</i> knockout results in reduced atherosclerosis. However, it remains unclear how <i>Twist1</i> affects EC phenotype and plaque biology.</p><p><strong>Methods: </strong>We performed EC lineage tracing, in situ analysis, and scRNA-Seq in <i>ApoE</i>^<i>-/</i>^<i>-</i> mice, both before disease and after 16 weeks of high-fat diet. We also performed these studies with 2 mouse models of EC <i>Twist1</i> deletion. We overexpressed <i>TWIST1</i> in human coronary artery ECs exposed to different flow conditions, followed by bulk RNA-seq. Human scRNA-Seq data were used to validate key findings in the mouse model.</p><p><strong>Results: </strong>We found that EC phenotypic modulation during atherosclerosis is characterized by both proinflammatory and endothelial-to-mesenchymal transition gene programs, occurring simultaneously along a single-cell fate transition. Human scRNA-Seq data validated a similar endothelial-to-mesenchymal transition during disease. We found that the commonly used <i>Twist1</i> conditional allele is hypomorphic, leading to reduced <i>Twist1</i> expression in multiple cell types. Using a mouse model of EC-specific <i>Twist1</i> deletion, we found reduced EC phenotypic modulation, decreased lesion size, and a more stable lesion phenotype. Integration of <i>TWIST1</i> overexpression in human coronary artery ECs with the mouse scRNA-seq data identified specific <i>TWIST1</i>-induced targets including CXCL12 and E-selectin during EC phenotypic modulation.</p><p><strong>Conclusions: </strong>Our study revealed important aspects of EC phenotypic modulation during atherosclerosis, unifying disparate observations in the field. We identified key cellular and molecular mechanisms underlying a top risk locus for multiple vascular diseases, highlighting the promotion of inflammatory endothelial-to-mesenchymal transition by <i>TWIST1</i> as a key driver of disease risk.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878858","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":"Cell-to-Cell Signaling Networks at the Blood-Brain Barrier in Health and Disease.","authors":"Joseph H McCarty","doi":"10.1161/ATVBAHA.126.324590","DOIUrl":"10.1161/ATVBAHA.126.324590","url":null,"abstract":"<p><p>The blood-brain barrier (BBB) is a highly specialized interface between the central nervous system and the peripheral circulation, crucial for maintaining neuronal homeostasis and protecting the brain parenchyma from potentially harmful blood-borne substances. This review examines the molecular and cellular organization of the BBB and explores how defective cell adhesion and signaling networks lead to BBB pathologies. I discuss the intricate architecture of brain endothelial cells within the context of the larger multicellular neurovascular unit, highlighting the roles of pericytes, astrocytes, as well as ECM (extracellular matrix) proteins and growth factors in vascular basement membranes. Recent advances in understanding endothelial cell tight junction dynamics, transport mechanisms, and communication pathways within the neurovascular unit are presented, with a particular emphasis on astrocyte-endothelial communication. Furthermore, I detail how abnormal astrocyte-endothelial signaling leads to BBB breakdown and contributes to various neurological disorders. In summary, this review synthesizes current knowledge of BBB biology, with particular emphasis on recent discoveries in signaling pathways, intercellular adhesion, and dynamic regulatory mechanisms that govern barrier function. By integrating findings from functional studies across multiple models, this review provides critical insights into both fundamental BBB biology and the potential development of translational approaches for treating human cerebrovascular disorders. Understanding these complex mechanisms not only advances our knowledge of normal brain homeostasis but also illuminates promising therapeutic targets and strategies for addressing conditions ranging from stroke to neurodegenerative diseases, ultimately paving the way for more effective clinical interventions that can preserve or restore BBB integrity.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544264/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878828","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":"MAP17 Orchestrates SGLT2-Dependent Glycolytic Reprogramming to Drive Trained Immunity and Accelerate Atherosclerosis.","authors":"Jianjin Wu, Lei Wang, Fukang Zou, Fangbing Liu, Guanyu Fang, Kai Cheng, Haochen Gao, Kangkang Zhi, Lefeng Qu","doi":"10.1161/ATVBAHA.126.324585","DOIUrl":"https://doi.org/10.1161/ATVBAHA.126.324585","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is driven by metabolic-immune crosstalk, in which trained immunity sustains vascular inflammation. MAP17 (membrane-associated protein 17), a redox- and metabolism-regulating adaptor protein, functions as a potential upstream driver of SGLT2 (sodium-glucose cotransporter 2). We aimed to determine whether MAP17 links hyperglycemia to glycolytic activation, inflammatory polarization, and plaque progression in atherosclerosis.</p><p><strong>Methods: </strong>MAP17 expression and its correlations with clinical risk factors were analyzed in serum from 30 patients with atherosclerosis. A trained immunity model was established in bone marrow-derived macrophages via sustained high glucose and IFN-γ (interferon-γ)/lipopolysaccharide stimulation. Functional assays were performed after MAP17 overexpression/knockdown, SGLT2 silencing, or glycolysis inhibition.</p><p><strong>Results: </strong>MAP17 was significantly coupregulated in patients with atherosclerosis, with the highest levels observed in those with concomitant diabetes or metabolic syndrome, and closely associated with elevated proinflammatory M1-like cytokines. Immunohistochemistry of carotid plaques confirmed its colocalization with SGLT2 within CD68⁺ macrophage-rich, lipid-laden, and inflamed regions. In bone marrow-derived macrophages, high glucose robustly induced MAP17 expression, which unidirectionally upregulated SGLT2, enhanced glycolytic flux, increased lactate production, and promoted M1-like polarization and foam cell formation. MAP17 knockdown markedly suppressed SGLT2 expression, glycolysis, and TNF-α (tumor necrosis factor-α)/IL (interleukin)-1β secretion, whereas MAP17 overexpression restored glycolytic activity, proinflammatory phenotype, and foam cell generation even in SGLT2-deficient cells. In diabetic chimeric <i>Apoe</i>^<i>-/-</i> mice, MAP17 activation correlated with increased glycolytic marker expression, higher proinflammatory M1-like macrophage ratios, aggravated vascular inflammation, and greater plaque burden; these effects were mitigated by MAP17 or SGLT2 silencing, or by glycolysis inhibition.</p><p><strong>Conclusions: </strong>MAP17 is a key upstream controller of the SGLT2-glycolysis axis that promotes trained immunity and accelerates atherosclerosis. Targeting MAP17 may disrupt the metabolic-inflammatory feedback loop and represents a promising therapeutic strategy for diabetic atherosclerosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878845","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":"Targeting Thrombopoietin/MPL Signaling to Mitigate JAK2V617F-Driven Cardiac Microvascular Disease.","authors":"Xiaoxi Yang, Kyla Masarik, Xiaochuan Sun, Fangfang Zhang, Kirsten Zheng, Haoyi Zheng, Huichun Zhan","doi":"10.1161/ATVBAHA.126.325061","DOIUrl":"https://doi.org/10.1161/ATVBAHA.126.325061","url":null,"abstract":"<p><strong>Background: </strong>Individuals with <i>JAK2V617F</i>-mutant myeloproliferative neoplasms or clonal hematopoiesis of indeterminate potential have a markedly increased risk of cardiovascular disease, yet the mechanisms by which mutant blood cells drive vascular and cardiac dysfunction remain incompletely understood. Although the thrombopoietin receptor MPL is central to hematopoiesis and is expressed in vascular endothelial cells (ECs), its role in JAK2V617F-associated cardiovascular complications is unknown.</p><p><strong>Methods: </strong>We generated chimeric mice with <i>JAK2V617F</i>-mutant blood cells and wild-type endothelium by bone marrow transplantation and challenged them with a high-fat/high-cholesterol diet to model cardiometabolic stress.</p><p><strong>Results: </strong>Mice with <i>JAK2V617F</i>-mutant blood cells developed a distinct cardiovascular phenotype characterized by microvascular disease, increased left ventricular mass, and relatively preserved left ventricular ejection fraction. Histopathologic analysis revealed coronary arteriole stenosis, perivascular fibrosis, reduced microvascular density, and endocardial injury, without evidence of epicardial coronary stenosis or myocardial infarction. Single-cell RNA sequencing revealed activation of inflammatory, stress-response, and endothelial-to-mesenchymal transition gene signatures in ECs, most prominently within the endocardial ECs. Immunohistochemistry identified MPL expression predominantly in endocardial ECs. Thrombopoietin/MPL signaling was upregulated in endocardial ECs in mice with <i>JAK2V617F</i>-mutant hematopoiesis, and treatment with an anti-MPL neutralizing antibody markedly improved cardiovascular pathology, restored endocardial integrity, and increased coronary microvascular density.</p><p><strong>Conclusions: </strong><i>JAK2V617F</i>-mutant hematopoiesis induces cardiac microvascular dysfunction under cardiometabolic stress. Endocardial ECs play a critical role in this pathological process, and endocardial MPL signaling constitutes a potential targetable pathway in JAK2V617F-associated cardiovascular disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":""},"PeriodicalIF":8.8,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148878818","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":"Angiogenesis in Lung Regeneration and Aging.","authors":"Priscilla Kyi, Mikaela Scheer, Tadanori Mammoto, Akiko Mammoto","doi":"10.1161/ATVBAHA.126.324410","DOIUrl":"10.1161/ATVBAHA.126.324410","url":null,"abstract":"<p><p>Angiogenesis, the formation of new capillary blood vessels, plays a key role in organ development and regeneration, while its dysregulation contributes to disease pathogenesis. In addition to the passive roles of blood vessels in gas exchange and nutrient delivery, endothelial cells regulate tissue homeostasis by secreting angiocrine factors that dictate the behaviors of surrounding cells to build tissue architecture. In the lung, endothelial cells closely interact with alveolar epithelial cells and other resident cells to coordinate signals necessary for alveolar regeneration. During aging, impaired angiogenic responses diminish tissue regeneration and injury repair, increasing susceptibility to chronic lung diseases. In addition to biochemical signals, dynamic changes in the mechanical forces also regulate pulmonary angiogenesis. In this brief review, we highlight the mechanisms by which endothelial cells maintain vascular homeostasis in the lung and how these processes become dysregulated with aging. We also discuss the impact of changes in the micromechanical environment and summarize recently developed new approaches for investigating endothelial cell signaling and cell-cell interactions in the human lung, which leads to the development of future therapeutic strategies.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324410"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13353207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410135","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":"Scube2 Modulates Coronary Vessel Formation During Cardiac Growth and Regeneration in Zebrafish.","authors":"Ke-Hsuan Wei, Ann Nee Lee, Kaushik Chowdhury, Muhammad Abdul Rouf, An-Ju Chu, Yu-Jen Hung, Ku-Chi Tsao, Yan-Ting Chen, Yuh-Charn Lin, Edita Bakūnaitė, Yao-Ming Chang, Darius Balciunas, Rubén Marín-Juez, Ruey-Bing Yang, Shih-Lei Ben Lai","doi":"10.1161/ATVBAHA.126.324944","DOIUrl":"10.1161/ATVBAHA.126.324944","url":null,"abstract":"<p><strong>Background: </strong>Coronary vessel formation is essential for cardiac growth and regeneration, yet the extracellular mechanisms coordinating coronary vascular remodeling remain incompletely understood. Scube2 (signal peptide-CUB [complement C1r/C1s, Uegf, Bmp1 (bone morphogenetic protein 1)]-EGF domain-containing protein 2) has been implicated in developmental vascular signaling, but its role in coronary vessel formation and cardiac regeneration has not been established.</p><p><strong>Methods: </strong>We investigated Scube2 function using zebrafish genetic loss-of-function mutants, inducible global and epicardial-specific dominant-negative models, cryoinjury-induced cardiac regeneration, confocal and ultrastructural imaging, bulk RNA sequencing, and biochemical analyses to examine signaling mechanisms.</p><p><strong>Results: </strong>Scube2 was expressed in the epicardium under homeostatic conditions and was rapidly induced in epicardial-derived cells following cardiac injury. Loss of Scube2 impaired developmental coronary vessel formation and caused myocardial ultrastructural abnormalities. Following injury, Scube2 deficiency resulted in defective revascularization, reduced mural cell association, decreased endothelial and cardiomyocyte proliferation, persistent fibrosis, and impaired cardiac regeneration. Temporal and epicardial-specific inhibition of Scube2 recapitulated these regenerative defects. Transcriptomic analyses identified dysregulation of VEGF (vascular endothelial growth factor) and PDGF (platelet-derived growth factor) signaling pathways, accompanied by reduced endothelial proliferation and prolonged inflammatory responses. Mechanistically, SCUBE2 interacted with PDGF-B (PDGF subunit B) and PDGFRβ (PDGF receptor β) and enhanced PDGFRβ activation, supporting a role in endothelial-mural cell communication during vascular remodeling.</p><p><strong>Conclusions: </strong>Scube2 is a critical regulator of coronary vessel formation and regenerative revascularization in zebrafish. By promoting PDGF-dependent endothelial-mural cell interactions, Scube2 coordinates vascular remodeling that supports myocardial regeneration. These findings identify Scube2 as a previously unrecognized regulator of coronary vascularization and suggest extracellular modulation of PDGF signaling as a potential therapeutic strategy to enhance cardiac repair after ischemic injury.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324944"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410191","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":"Aortic Stenosis Hyalectan Remodeling Revealed by Proteomics and Glycoproteomics.","authors":"Siqi Yin, Ursula Mayr, Javier Barallobre-Barreiro, Elisa Duregotti, Anna K Barton, Rong Bing, Dyana Markose, Xiaoke Yin, Padmini Sarathchandra, Bhawana Singh, Wen-Yu Lin, Marika Fava, Lukas E Schmidt, Ferheen Baig, Ajay M Shah, Konstantinos Theofilatos, Najma Latif, Christian Hengstenberg, Tamás Radovits, Béla Merkely, Neil C Henderson, Marc R Dweck, Manuel Mayr","doi":"10.1161/ATVBAHA.126.323867","DOIUrl":"10.1161/ATVBAHA.126.323867","url":null,"abstract":"<p><strong>Background: </strong>Calcific aortic valve (AV) disease (CAVD) is recognized as an active pathological process involving extracellular matrix remodeling. This study investigates extracellular matrix remodeling through proteomic analysis and a novel mouse model of aortic stenosis.</p><p><strong>Methods: </strong>Proteomic and glycoproteomic analyses were conducted on AV leaflets from heart transplant donors (n=29) and patients with CAVD (n=17). Each CAVD sample was subdivided into noncalcified and calcified regions. To investigate the functional impact of extracellular matrix remodeling on aortic stenosis, we crossed apolipoprotein E-deficient mice (<i>ApoE</i>^<i>-/-</i>) with mice lacking the catalytic domain of ADAMTS5 (<i>Adamts5</i>^<i>Δcat</i>) to generate a mouse model combining hyalectan accumulation with hypercholesterolemia.</p><p><strong>Results: </strong>Proteomic and glycoproteomic analyses revealed hyalectan accumulation in CAVD compared with control valves. Versican predominated in noncalcified regions, while aggrecan was enriched in calcified regions. The shift in hyalectan composition correlated with changes in AV pressure gradient, elevated osteoblast-like cell markers, and inflammatory proteins, most notably pentraxin 3. Both versican and aggrecan are characterized by their ability to bind hyaluronan and serve as substrates of ADAMTS5. In <i>Adamts5</i>^<i>Δcat</i><i>/ApoE</i>^<i>-</i>^<i>/-</i> mice, hyalectan accumulation was associated with narrowed aortic cusp separation and increased post-AV velocity. Proteomic analysis of AVs from <i>Adamts5</i>^<i>Δcat</i><i>/ApoE</i>^<i>-</i>^<i>/-</i> mice revealed elevated versican, aggrecan, and pentraxin 3, recapitulating key features of human CAVD. Single-cell RNA sequencing and in vitro experiments linked versican to activated valve interstitial cells, while aggrecan colocalized with calcification markers in osteoblast-like cells. Pentraxin 3 was bound to hyaluronan and accumulated in calcified AVs. ADAMTS5 deficiency was sufficient to cause intact versican accumulation and promote valve interstitial cell activation, accompanied by increased expression of osteopontin. Osteopontin is a ligand of CD44, a principle hyaluronan receptor.</p><p><strong>Conclusions: </strong>This study highlights hyaluronan remodeling during aortic stenosis pathogenesis. A shift from versican to aggrecan in human CAVD correlates with changes in AV pressure gradient. In <i>Adamts5</i>^<i>Δcat</i><i>/ApoE</i>^<i>-</i>^<i>/-</i> mice, impaired hyalectan catabolism promotes aortic stenosis.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e323867"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13506200/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454371","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 BMP-Regulated Cell Differentiation in the Aortic Media by Mutating Matrix Gla Protein.","authors":"Xinjiang Cai, Kavinda K J Gunasinghe, Lei Qi, Li Zhang, Xiuju Wu, Zheng Jing, Yan Zhao, Hannah Kim, Eddy Yao, Tzung K Hsiai, Taufiq Rahman, Xavier W Chee, Yucheng Yao, Kristina I Boström","doi":"10.1161/ATVBAHA.126.324621","DOIUrl":"10.1161/ATVBAHA.126.324621","url":null,"abstract":"<p><strong>Background: </strong>MGP (matrix Gla protein) serves as an inhibitor of vascular calcification by limiting elastin degradation and regulating BMP (bone morphogenetic protein) activity. Mutation of the conserved proline residue 64 to glycine in MGP abolishes BMP binding in vitro. We hypothesized that selective loss of BMP binding would elucidate the contribution of BMP to cell differentiation in <i>Mgp</i>-deficient mice.</p><p><strong>Methods: </strong>Computational analyses using AlphaFold3 and molecular dynamics simulations were performed to determine the structural effects of γ-carboxylation and the proline residue 64 to glycine mutation. The vascular phenotype of <i>Mgp</i>-knockin mice expressing the proline residue 64 to glycine mutation was compared with wild-type (WT) and global <i>Mgp</i>-knockout mice. Proximity ligation assay was performed to assess MGP-BMP4 in aortic cells. Single-cell RNA-sequencing was used to identify cellular alterations in the vascular media.</p><p><strong>Results: </strong>Molecular dynamics simulation revealed 5 Ca²⁺ ions coordinated by γ-carboxylated Glu residues in the MGP dimer. The proline residue 64 to glycine mutation did not disrupt Ca²⁺ binding but likely suppressed conformational changes required for BMP4 binding. Unlike <i>Mgp</i>-<i>KO</i> mice, <i>Mgp</i>-knockin mice did not develop vascular calcification, elastic lamina proteolysis, and endothelial-mesenchymal transition, but exhibited vascular fibrosis. MGP-BMP4 interaction observed in WT aortic cells was barely detectable in <i>Mgp</i>-knockin aortic cells. Single-cell RNA-sequencing revealed increased fractions of smooth muscle cells and enhanced myofibroblast differentiation in the <i>Mgp</i>-knockin aortas compared with WT. In <i>Mgp</i>-knockin aortas, SMAD2 expression was significantly increased throughout the vessel wall compared with WT aortas. In contrast, SMAD1/5/9 activation in the <i>Mgp</i>-knockout aortas was more confined to the endothelium, whereas it localized to the media-adventitia transition in WT and <i>Mgp</i>-knockin aortas. Both <i>Mgp</i>-knockin and <i>Mgp</i>-knockout mice developed arteriovenous malformations in the lungs, kidneys, and brain.</p><p><strong>Conclusions: </strong>Our findings suggest that MGP plays a versatile role in preserving vascular integrity, in part serving as an important BMP-trap aimed at directing vascular cell differentiation.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e324621"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13506195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454348","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":"Endothelial Cell-Pericyte Crosstalk in the Brain Balances Microvascular Stability and Plasticity.","authors":"Jihui Lee, Emily Luc, Amber N Stratman","doi":"10.1161/ATVBAHA.126.323547","DOIUrl":"10.1161/ATVBAHA.126.323547","url":null,"abstract":"<p><p>Pericytes are mural cells that broadly support microvascular integrity and are essential contributors to the neurovascular unit in the brain. They contribute to blood-brain barrier function, endothelial behavior, and microvascular tone, and their dysfunction is implicated in cardiometabolic and neurovascular disease. However, pericytes remain difficult to directly manipulate due to heterogeneous identity, overlapping marker expression with other mural and stromal cells, and context-dependent functional behaviors. Here, we propose that pericytes are best understood as dynamic regulators of microvascular state rather than a static cell type. Pericyte behaviors span a spectrum of functional states associated with vascular stability, angiogenesis, contractility, and fibrosis, and transitions between these functions shape microvascular remodeling in development, homeostasis, and disease. In their stabilization state, pericytes support blood-brain barrier integrity and microvascular stability, and when disrupted, can contribute to small vessel disease and neurodegeneration. Conversely, a plastic pericyte state is often associated with angiogenesis and ischemia-reperfusion responses, but can also contribute to fibrotic remodeling. Finally, we discuss how experimental systems, including in vitro and in vivo models, inform the interpretation of pericyte function and state. This perspective provides a framework for interpreting pericyte biology in the context of endothelial cell function and suggests that targeting pericyte state dynamics may offer new opportunities to protect the microvasculature in response to cardiometabolic and neurovascular disease.</p>","PeriodicalId":8401,"journal":{"name":"Arteriosclerosis, Thrombosis, and Vascular Biology","volume":" ","pages":"e323547"},"PeriodicalIF":8.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13426066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148618357","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}