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Vascular biology

  • 327 Articles
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Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis
Dyuti Saha, … , Praveen K. Vemula, Colin Jamora
Dyuti Saha, … , Praveen K. Vemula, Colin Jamora
Published June 20, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI177123.
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Angiopoietin-like protein 2 mediates vasculopathy driven fibrogenesis in a mouse model of systemic sclerosis

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Abstract

Vasculopathy is a common hallmark of various fibrotic disorders including systemic sclerosis (SSc), yet its underlying etiology and contribution to fibrogenesis remain ill-defined. In SSc the vasculopathy typically precedes the onset of fibrosis and we observed that this phenomenon is recapitulated in the Snail transgenic mouse model of SSc. The vascular anomalies manifest as deformed vessels, endothelial cell dysfunction and vascular leakage. Our investigation into the underlying mechanism of this phenotype revealed that angiopoietin-like protein 2 (ANGPTL2), secreted by the Snail transgenic keratinocytes, is a principal driver of fibrotic vasculopathy. In endothelial cells, ANGPTL2 upregulates pro-fibrotic genes, downregulates various junctional proteins, and prompts the acquisition of mesenchymal characteristics. Inhibiting endothelial cell junctional instability and consequently vascular leakage with a synthetic analog of the microbial metabolite Urolithin A (UAS03) effectively mitigated the vasculopathy and inhibited fibrogenesis. Thus, ANGPTL2 emerges as a promising early biomarker of the disease and inhibiting the vasculopathy inducing effects of this protein with agents such as UAS03 presents an appealing therapeutic avenue to reduce disease severity. These insights hold the potential to revolutionize the approach to the treatment of fibrotic diseases by targeting the vascular defects.

Authors

Dyuti Saha, Ravi Kiran Annadorai, Sujaya Thannimangalath, Neha P. Shroff, Sunny Kataria, Binita Dam, Abhik Dutta, Akshay Hegde, Ankita Hiwale, Venkatesh Ravula, Shagnik Saha, Lekshmi Minikumari Rahulan, Neha Nigam, Neha Singh, Vikas Agarwal, Praveen K. Vemula, Colin Jamora

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Myeloid-mediated cerebral amyloid vasculitis and the potential role of the immune response in brain atrophy
Rudy J. Castellani, … , Amy B. Heimberger, Pouya Jamshidi
Rudy J. Castellani, … , Amy B. Heimberger, Pouya Jamshidi
Published June 19, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI195137.
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Myeloid-mediated cerebral amyloid vasculitis and the potential role of the immune response in brain atrophy

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Abstract

Authors

Rudy J. Castellani, Hinda Najem, Amy B. Heimberger, Pouya Jamshidi

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Hemodynamic forces prevent myxomatous valve disease in mice through KLF2/4 signaling
Jesse A. Pace, … , Giovanni Ferrari, Mark L. Kahn
Jesse A. Pace, … , Giovanni Ferrari, Mark L. Kahn
Published June 16, 2025
Citation Information: J Clin Invest. 2025;135(12):e186593. https://doi.org/10.1172/JCI186593.
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Hemodynamic forces prevent myxomatous valve disease in mice through KLF2/4 signaling

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Abstract

Myxomatous valve disease (MVD) is the most common form of cardiac valve disease in the developed world. A small fraction of MVD is syndromic and arises in association with matrix protein defects such as those in Marfan syndrome, but most MVD is acquired later in life through an undefined pathogenesis. The KLF2/4 transcription factors mediate endothelial fluid shear responses, including those required to create cardiac valves during embryonic development. Here we test the role of hemodynamic shear forces and downstream endothelial KLF2/4 in mature cardiac valves. We find that loss of hemodynamic forces in heterotopically transplanted hearts or genetic deletion of KLF2/4 in cardiac valve endothelium confers valve cell proliferation and matrix deposition associated with valve thickening, findings also observed in mice expressing the mutant fibrillin-1 protein known to cause human MVD. Transcriptomic and histologic analysis reveals increased monocyte recruitment and TGF-β signaling in both fibrillin-1–mutant valves and valves lacking hemodynamic forces or endothelial KLF2/4 function, but only loss of TGF-β/SMAD signaling rescued myxomatous changes. We observed reduced KLF2/4 expression and augmented SMAD signaling in human MVD. These studies identify hemodynamic activation of endothelial KLF2/4 as an environmental homeostatic regulator of cardiac valves and suggest that non-syndromic MVD may arise in association with disturbed blood flow across the aging valve.

Authors

Jesse A. Pace, Lauren M. Goddard, Courtney C. Hong, Liqing Wang, Jisheng Yang, Mei Chen, Yitian Xu, Martin H. Dominguez, Siqi Gao, Xiaowen Chen, Patricia Mericko-Ishizuka, Can Tan, Tsutomu Kume, Wenbao Yu, Kai Tan, Wayne W. Hancock, Giovanni Ferrari, Mark L. Kahn

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Modulation of the Acod1/itaconate pathway differentially affects atherosclerosis severity across genetic models and sexes
Lara Haase, … , Johannes Meiser, Jochen G. Schneider
Lara Haase, … , Johannes Meiser, Jochen G. Schneider
Published June 12, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI182472.
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Modulation of the Acod1/itaconate pathway differentially affects atherosclerosis severity across genetic models and sexes

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Abstract

Authors

Lara Haase, Anouar Belkacemi, Laura Neises, Nicole Kiweler, Christine Wesely, Rosanna Huchzermeier, Maja Bozic, Arefeh Khakdan, Marta Sánchez, Arnaud Mary, Nadja Sachs, Hanna Winter, Enrico Glaab, Michael T. Heneka, Emiel P.C. van der Vorst, Michel Mittelbronn, Johannes Meiser, Jochen G. Schneider

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Diet-induced obesity promotes endothelial cell desensitization to VEGF-A and permanent islet vessel dysfunction in mice
Yan Xiong, … , Erwin Ilegems, Per-Olof Berggren
Yan Xiong, … , Erwin Ilegems, Per-Olof Berggren
Published June 9, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI177601.
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Diet-induced obesity promotes endothelial cell desensitization to VEGF-A and permanent islet vessel dysfunction in mice

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Abstract

Pancreatic islet microvasculature is essential for optimal islet function and glucose homeostasis. However, islet vessel pathogenesis in obesity and its role in the manifestation of metabolic disorders remain understudied. Here, we depict the time-resolved decline of intra-islet endothelial cell responsiveness to vascular endothelial cell growth factor A (VEGF-A) and islet vessel function in a mouse model of diet-induced obesity. Longitudinal imaging of sentinel islets transplanted into mouse eyes revealed substantial vascular remodeling and diminished VEGF-A response in islet endothelial cells after 12 weeks of western diet (WD) feeding. This led to islet vessel barrier dysfunction and hemodynamic dysregulation, delaying transportation of secreted insulin into the blood. Notably, islet vessels exhibited a metabolic memory of previous WD feeding. Neither VEGF-A sensitivity nor the other vascular alterations was fully restored by control diet (CD) refeeding, resulting in modest yet significant impairment in glucose clearance despite normalized insulin sensitivity. Mechanistic analysis implicated hyperactivation of atypical protein kinase C (aPKC) under both WD and recovery conditions, which inhibited VEGF receptor 2 (VEGFR2) internalization and blunted VEGF-A triggered signal transduction in endothelial cells. In summary, prolonged WD feeding causes irreversible islet endothelial cell desensitization to VEGF-A and islet vessel dysfunction, directly undermining glucose homeostasis.

Authors

Yan Xiong, Andrea Dicker, Montse Visa, Erwin Ilegems, Per-Olof Berggren

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PIEZO1 mediates mechanical reprogramming of neutrophils for proangiogenic specialization in the lung
Jin Wang, … , Bin Li, Jing Wang
Jin Wang, … , Bin Li, Jing Wang
Published June 2, 2025
Citation Information: J Clin Invest. 2025;135(11):e183796. https://doi.org/10.1172/JCI183796.
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PIEZO1 mediates mechanical reprogramming of neutrophils for proangiogenic specialization in the lung

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Abstract

Neutrophils are the most abundant immune cells that constantly patrol or marginate inside vascular beds to support immune homeostasis. The extent to which neutrophils undergo reprogramming in response to the changes in vascular architecture and the resultant biological implications of such adaptations remain unclear. Here, we performed intravital imaging and transcriptional profiling to investigate neutrophil behavior across different tissues. Our findings revealed that neutrophils had significant deformability and spontaneous calcium signaling while navigating through the narrow pulmonary vessels. Pulmonary neutrophils exhibited unique transcriptional profiles and were specialized for proangiogenic functions. We found that the mechanosensitive ion channel Piezo-type mechanosensitive ion channel component 1 (PIEZO1) was essential for neutrophil reprogramming. Deletion of Piezo1 in neutrophils ablated the lung-specific proangiogenic transcriptional signature and impaired capillary angiogenesis in both physiological and pathological conditions. Collectively, these data show that mechanical adaptation of neutrophils within the pulmonary vasculature drives their reprogramming in the lungs and promotes pulmonary vascular homeostasis.

Authors

Jin Wang, Wenying Zhao, Wenjuan Bai, Dong Dong, Hui Wang, Xin Qi, Ajitha Thanabalasuriar, Youqiong Ye, Tian-le Xu, Hecheng Li, Paul Kubes, Bin Li, Jing Wang

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Asparagine endopeptidase cleaves apolipoprotein A1 and accelerates pathogenesis of atherosclerosis
Mengmeng Wang, … , Xifei Yang, Keqiang Ye
Mengmeng Wang, … , Xifei Yang, Keqiang Ye
Published May 15, 2025
Citation Information: J Clin Invest. 2025;135(10):e185128. https://doi.org/10.1172/JCI185128.
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Asparagine endopeptidase cleaves apolipoprotein A1 and accelerates pathogenesis of atherosclerosis

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Abstract

Atherosclerosis is a slowly progressing inflammatory disease characterized with cholesterol disorder and intimal plaques. Asparagine endopeptidase (AEP) is an endolysosomal protease that is activated under acidic conditions and is elevated substantially in both plasma and plaques of patients with atherosclerosis. However, how AEP accelerates atherosclerosis development remains incompletely understood, especially from the view of cholesterol metabolism. This project aims to reveal the crucial substrate of AEP during atherosclerosis plaque formation and to lay the foundation for developing novel therapeutic agents for Atherosclerosis. Here, we show that AEP is augmented in the atherosclerosis plaques obtained from patients and proteolytically cuts apolipoprotein A1 (APOA1) and impairs cholesterol efflux and high-density lipoprotein (HDL) formation, facilitating atherosclerosis pathologies. AEP is activated in the liver and aorta of apolipoprotein E–null (APOE-null) mice, and deletion of AEP from APOE–/– mice attenuates atherosclerosis. APOA1, an essential lipoprotein in HDL for cholesterol efflux, is cleaved by AEP at N208 residue in the liver and atherosclerotic macrophages of APOE–/– mice. Blockade of APOA1 cleavage by AEP via N208A mutation or its specific inhibitor, #11a, substantially diminishes atherosclerosis in both APOE–/– and LDLR–/– mice. Hence, our findings support that AEP disrupts cholesterol metabolism and accelerates the development of atherosclerosis.

Authors

Mengmeng Wang, Bowei Li, Shuke Nie, Xin Meng, Guangxing Wang, Menghan Yang, Wenxin Dang, Kangning He, Tucheng Sun, Ping Xu, Xifei Yang, Keqiang Ye

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Thrombospondin-1 inhibits alternative complement pathway activation in antineutrophil cytoplasmic antibody-associated vasculitis
Swagata Konwar, … , Todor Tschongov, Karsten Häffner
Swagata Konwar, … , Todor Tschongov, Karsten Häffner
Published May 8, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI180062.
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Thrombospondin-1 inhibits alternative complement pathway activation in antineutrophil cytoplasmic antibody-associated vasculitis

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Abstract

Complement activation is a relevant driver in the pathomechanisms of vasculitis. The involved proteins in the interaction between endothelia, complement and platelets in these conditions are only partially understood. Thrombospondin-1 (TSP-1), found in platelet α-granules and released from activated endothelial cells, interacts with factor H (FH) and von Willebrand factor (vWF). However, direct regulatory interaction with the complement cascade has not yet been described. We could show that TSP-1 is a potent, FH-independent inhibitor of the alternative complement pathway. TSP-1 binds to complement proteins, inhibits cleavage of C3 and C5 and the formation of the membrane attack complex. Complement-regulatory function is validated in blood samples from patients with primary complement defects. Physiological relevance of TSP-1 is demonstrated in ANCA-associated vasculitis (AAV) patients by significantly enhanced TSP-1 staining in glomerular lesions and increased complement activity and NETosis following TSP-1 deficiency in an in vitro and in vivo model of AAV. The newly described complement-inhibiting function of TSP-1 represents an important mechanism in the interaction of endothelia and complement. In particular, the interplay between released TSP-1 and the complement system locally, especially on surfaces, influences the balance between complement activation and inhibition and may be relevant in various vascular diseases.

Authors

Swagata Konwar, Sophie Schroda, Manuel Rogg, Jessika Kleindienst, Eva L. Decker, Martin Pohl, Barbara Zieger, Jens Peter Panse, Hong Wang, Robert Grosse, Christoph Schell, Sabine Vidal, Xiaobo Liu, Christian Gorzelanny, Todor Tschongov, Karsten Häffner

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Lymphatic dysfunction in lupus contributes to cutaneous photosensitivity and lymph node B cell responses
Mir J. Howlader, … , Babak J. Mehrara, Theresa T. Lu
Mir J. Howlader, … , Babak J. Mehrara, Theresa T. Lu
Published April 22, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI168412.
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Lymphatic dysfunction in lupus contributes to cutaneous photosensitivity and lymph node B cell responses

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Abstract

Patients with systemic lupus erythematosus (SLE) are photosensitive, developing skin inflammation with even ambient ultraviolet radiation (UVR), and this cutaneous photosensitivity can be associated with UVR-induced flares of systemic disease, which can involve increased autoantibodies and further end organ injury. Mechanistic insight into the link between the skin responses and autoimmunity is limited. Signals from skin are transmitted directly to the immune system via lymphatic vessels, and here we show evidence for potentiation of UVR-induced lymphatic flow dysfunction in SLE patients and murine models. Improving lymphatic flow by manual lymphatic drainage (MLD) or with a transgenic model with increased lymphatic vessels reduces both cutaneous inflammation and lymph node B and T cell responses, and long term MLD reduces splenomegaly and titers of a number of autoantibodies. Mechanistically, improved flow restrains B cell responses in part by stimulating a lymph node fibroblastic reticular cell-monocyte axis. Our results point to lymphatic modulation of lymph node stromal function as a link between photosensitive skin responses and autoimmunity and as a therapeutic target in lupus, provide insight into mechanisms by which the skin state regulates draining lymph node function, and suggest the possibility of MLD as an accessible and cost-effective adjunct to add to ongoing medical therapies for lupus and related diseases.

Authors

Mir J. Howlader, William G. Ambler, Madhavi Latha S. Chalasani, Aahna Rathod, Ethan S. Seltzer, Ji Hyun Sim, Jinyeon Shin, Noa Schwartz, William D. Shipman III, Dragos C. Dasoveanu, Camila B. Carballo, Ecem Sevim, Salma Siddique, Yurii Chinenov, Scott A. Rodeo, Doruk Erkan, Raghu P. Kataru, Babak J. Mehrara, Theresa T. Lu

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HINT1 aggravates aortic aneurysm by targeting ITGA6/FAK axis in vascular smooth muscle cells
Yan Zhang, … , Liping Xie, Yong Ji
Yan Zhang, … , Liping Xie, Yong Ji
Published April 8, 2025
Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI186628.
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HINT1 aggravates aortic aneurysm by targeting ITGA6/FAK axis in vascular smooth muscle cells

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Abstract

Aortic aneurysm is a high-risk cardiovascular disease without effective cure. Vascular Smooth Muscle Cell (VSMC) phenotypic switching is a key step in the pathogenesis of aortic aneurysm. Here, we revealed the role of histidine triad nucleotide-binding protein 1 (HINT1) in aortic aneurysm. HINT1 was upregulated both in aortic tissue from patients with aortic aneurysm and Ang II-induced aortic aneurysm mice. VSMC-specific HINT1 deletion alleviated aortic aneurysm via preventing VSMC phenotypic switching. With the stimulation of pathological factors, the increased nuclear translocation of HINT1 mediated by nucleoporin 98 (Nup98) promoted the interaction between HINT1 and transcription factor AP-2 alpha (TFAP2A) and further triggered the transcription of integrin alpha 6 (ITGA6) mediated by TFAP2A, and consequently activated the downstream focal adhesion kinase (FAK)/STAT3 signal pathway, leading to aggravation of VSMC phenotypic switching and aortic aneurysm. Importantly, Defactinib treatment was demonstrated to limit aortic aneurysm development by inhibiting the FAK signal pathway. Thus, HINT1/ITGA6/FAK axis emerges as potential therapeutic strategies in aortic aneurysm.

Authors

Yan Zhang, Wencheng Wu, Xuehui Yang, Shanshan Luo, Xiaoqian Wang, Qiang Da, Ke Yan, Lulu Hu, Shixiu Sun, Xiaolong Du, Xiaoqiang Li, Zhijian Han, Feng Chen, Aihua Gu, Liansheng Wang, Zhiren Zhang, Bo Yu, Chenghui Yan, Yaling Han, Yi Han, Liping Xie, Yong Ji

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MiR-33 fine-tunes atherosclerotic plaque inflammation
Mireille Ouimet, Hasini Ediriweera, and colleagues show that miR-33 controls the macrophage inflammatory program and promotes atherosclerotic plaque development…
Published October 26, 2015
Scientific Show StopperVascular biology

Contracting lacteals send lipids down the drain
Kibaek Choe, Jeon Yeob Jang, Intae Park and colleagues visualize lipid drainage through lacteals using intravital, video-rate microscopy…
Published October 5, 2015
Scientific Show StopperVascular biology

FOXC2 keeps lymphatic vessels leak-proof
Amélie Sabine and colleagues demonstrate that disturbed flow in lymphatic vasculature induces expression of the transcription factor FOXC2, which is essential for maintaining normal endothelial cell morphology and vessel integrity…
Published September 21, 2015
Scientific Show StopperVascular biology

Venous malformation model provides therapeutic insight
Elisa Boscolo and colleagues develop a murine model of venous malformation and demonstrate that rapamycin improves clinical symptoms of in this model and in patients…
Published August 10, 2015
Scientific Show StopperVascular biology

Lymphatic valves grow with the flow
Daniel Sweet and colleagues reveal that lymph flow is essential for lymphatic vessel maturation…
Published July 27, 2015
Scientific Show StopperVascular biology

GATA2 serves as a lymphatic rheostat
Jan Kazenwadel, Kelly Betterman, and colleagues reveal that the transcription factor GATA2 is essential for lymphatic valve development and maintenance…
Published July 27, 2015
Scientific Show StopperVascular biology

Factoring in factor XII in hereditary angioedema III
Jenny Björkqvist and colleagues elucidate the mechanism by which hereditary angioedema III-associated factor XII promotes vascular leakage…
Published July 20, 2015
Scientific Show StopperVascular biology

Regional regulation of atherosclerosis
Yogendra Kanthi, Matthew Hyman, and colleagues reveal that CD39 is regulated by blood flow and is protective against atherosclerosis…
Published June 29, 2015
Scientific Show StopperVascular biology
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