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Protein disulfide isomerase cleaves allosteric disulfides in histidine-rich glycoprotein to regulate thrombosis
Vascular protein disulfide isomerase (PDI) regulates thrombosis and targeting extracellular PDI remains a promising antithrombotic approach. Here, the authors show that PDI cleaves allosteric disulfides on histidine-rich glycoprotein to influence its functions during coagulation and thus fine-tune the kinetics of thrombus formation.
- Keyu Lv
- , Shuai Chen
- & Chao Fang
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Article
| Open Access
Genetic associations of protein-coding variants in venous thromboembolism
Here, the authors perform a large exome-wide study for venous thromboembolism and identify 18 potential risk genes, including 4 new genes, revealing a significant role of rare coding variants, and offering insights into genetic risk factors.
- Xiao-Yu He
- , Bang-Sheng Wu
- & Jin-Tai Yu
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Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence
Ferroptosis is a novel form of regulated cell death associated with lipid oxidation. Here, the authors demonstrate that the proferroptosis signal is activated and drives vascular aging by inducing senescence in vascular smooth muscle cells.
- Di-Yang Sun
- , Wen-Bin Wu
- & Pei Wang
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Palmitic acid in type 2 diabetes mellitus promotes atherosclerotic plaque vulnerability via macrophage Dll4 signaling
Patients with Type 2 Diabetes Mellitus are increasingly susceptible to atherosclerotic plaque vulnerability. Here, the authors show that elevated palmitic acid levels are linked to increased atherosclerotic plaque vulnerability.
- Xiqiang Wang
- , Ling Zhu
- & Zhongwei Liu
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Article
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Resolvin T4 enhances macrophage cholesterol efflux to reduce vascular disease
Specialized pro-resolving mediators (SPM) are involved in the reprogramming of immune responses. Here the authors show that resolvin (RvT) 4 limits the progression of vascular disease in mouse models of arthritis exacerbated atherosclerotic inflammation.
- Mary E. Walker
- , Roberta De Matteis
- & Jesmond Dalli
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Article
| Open Access
A drug-free cardiovascular stent functionalized with tailored collagen supports in-situ healing of vascular tissues
The efficacy of drug-eluting stents remains limited due to delayed reendothelialization, impaired intimal remodeling, and potentially increased late restenosis. Here the authors propose a one-produces-multi stent coating, a drug-free strategy that supports in situ healing of vascular tissues, as demonstrated in rabbit and porcine models.
- Haoshuang Wu
- , Li Yang
- & Yunbing Wang
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15-Lipoxygenase promotes resolution of inflammation in lymphedema by controlling Treg cell function through IFN-β
Specialised pro-resolving lipid mediators can reduce inflammatory responses and may be active in lymphedema. Here the authors show that in a mouse model 15-LO derived lipid mediators are reduced during inflammation and that a lack of the 15-LO producing enzyme aggravated disease and addition of 15-LO enzyme or Treg cells reduced disease.
- A. Zamora
- , M. Nougué
- & B. Garmy-Susini
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| Open Access
Atherosclerotic plaque development in mice is enhanced by myeloid ZEB1 downregulation
Accumulation of lipid-laden macrophages in the arterial wall is a critical step in atherosclerosis. Here, the authors show that downregulation of Zeb1 in macrophages promotes lipid accumulation and atherosclerotic plaque formation while its restoration with macrophage-targeted nanoparticles reverses these effects.
- M. C. Martinez-Campanario
- , Marlies Cortés
- & Antonio Postigo
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Choroidal and retinal thinning in chronic kidney disease independently associate with eGFR decline and are modifiable with treatment
In patients with CKD, there is an unmet need for biomarkers that reliably track kidney injury. Here, in a series of prospective studies, the authors show that retinal OCT metrics reflect kidney injury, are modified by treatments for kidney disease and can predict future decline of kidney function.
- Tariq E. Farrah
- , Dan Pugh
- & Neeraj Dhaun
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Reduced FOXF1 links unrepaired DNA damage to pulmonary arterial hypertension
It is unknown whether unrepaired DNA damage in lung endothelial cells causes persistent pulmonary arterial hypertension. Here, the authors combine oxidative stress with impaired BMPR2 signaling to link a reduction in FOXF1 to unrepaired DNA damage and impaired regeneration of normal endothelium.
- Sarasa Isobe
- , Ramesh V. Nair
- & Marlene Rabinovitch
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| Open Access
Mutation of key signaling regulators of cerebrovascular development in vein of Galen malformations
Vein of Galen malformations (VOGMs) are severe congenital brain arteriovenous malformations. Here the authors work to elucidate the pathogenesis of VOGMs by performing an integrated analysis of 310 VOGM proband family exomes and 336,326 human cerebrovasculature single-cell transcriptomes to identify mutations of key signaling regulators.
- Shujuan Zhao
- , Kedous Y. Mekbib
- & Kristopher T. Kahle
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Enhanced pericyte-endothelial interactions through NO-boosted extracellular vesicles drive revascularization in a mouse model of ischemic injury
Treatment alternatives are not available for a significant portion of critical limb ischemia patients. Here, the authors show a strategy to engineer mesenchymal stem cells-derived extracellular vesicles to induce revascularization in mice.
- Ling Guo
- , Qiang Yang
- & Min Feng
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Article
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Healthy dietary patterns and the risk of individual chronic diseases in community-dwelling adults
Dietary patterns have been linked to a limited number of major chronic diseases. Here, the authors show greater adherence to healthy dietary patterns, especially Alternate Mediterranean Diet, is associated with a lower risk of most of the 48 tested chronic diseases.
- Xianwen Shang
- , Jiahao Liu
- & Mingguang He
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Activation of coagulation and proinflammatory pathways in thrombosis with thrombocytopenia syndrome and following COVID-19 vaccination
Adenovirus-based vaccination for SARS-CoV-2 has a rare chance to cause thrombosis with thrombocytopenia (TTS). Here the authors compare proteomic and transcriptomic data from vaccinated participants with or without TTS to find distinct activations of coagulation and innate immune pathways in patient with TTS, or following initial or boosting vaccination.
- Malika Aid
- , Kathryn E. Stephenson
- & Dan H. Barouch
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Hypersensitive MR angiography based on interlocking stratagem for diagnosis of cardiac-cerebral vascular diseases
Current contrast-enhanced magnetic resonance angiography approaches are sub-optimal. Here the authors present a hypersensitive MR angiography strategy based on interlocking stratagem of zwitterionic Gd-chelate contrast agents (PAA-Gd), enabling sophisticated micro-vessel angiography of cardiac-cerebrovascular diseases with ultrahigh resolution.
- Peisen Zhang
- , Junwei Cheng
- & Yi Hou
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Article
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Endothelial Sp1/Sp3 are essential to the effect of captopril on blood pressure in male mice
Hypertension is the leading risk factor for cardiovascular disease, which represents the top cause of morbidity and mortality worldwide. Here, the authors show deletion of endothelial Sp1 and Sp3 leads to a disruption in endothelium-dependent vasodilation and the onset of hypertension, which abolishes the beneficial actions of captopril.
- Hanlin Lu
- , Xiuxin Jiang
- & Wencheng Zhang
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FAM3A reshapes VSMC fate specification in abdominal aortic aneurysm by regulating KLF4 ubiquitination
The mechanisms underlying vascular smooth muscle cell reprogramming in abdominal aortic aneurism (AAA) remain unclear. Here they show that FAM3A, a metabolic cytokine, serves as a cell fate-shaping regulator of smooth muscle cells to protect against AAA formation.
- Chuxiang Lei
- , Haoxuan Kan
- & Yuehong Zheng
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Article
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Macrophage-to-endothelial cell crosstalk by the cholesterol metabolite 27HC promotes atherosclerosis in male mice
Hypercholesterolemia and vascular inflammation both contribute to the pathogenesis of atherosclerosis, but how hypercholesterolemia initiates vascular inflammation is not fully understood. Here the authors report that crosstalk between macrophages and endothelial cells mediated by the cholesterol metabolite 27-hydroxycholesterol drives vascular inflammation and contributes to atherosclerosis in male mice.
- Liming Yu
- , Lin Xu
- & Philip W. Shaul
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Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism
Improved biomarker-based tools for diagnosis and risk prediction of venous thromboembolism (VTE) are needed. Here, the authors show that Complement Factor H Related 5 protein, a regulator of the alternative pathway of complement activation, is a VTE-associated plasma biomarker in 5 independent cohorts.
- Maria Jesus Iglesias
- , Laura Sanchez-Rivera
- & Jacob Odeberg
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Article
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AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling
Thoracic aortic aneurysm (TAA) causes many sudden deaths each year, however, no effective drug treatment is available. Here, the authors show that AGGF1 protein therapy attenuates TAA in three different mouse models through integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signalling.
- Xingwen Da
- , Ziyan Li
- & Qing K. Wang
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MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ
Life-threatening vascular tumors can be associated with uncontrolled activity of the guanine nucleotide-binding protein subunit alpha (Gαq). Here, the authors develop a murine model for these tumors and show that MEK inhibition prevents formation of vascular lesions and improves survival.
- Sandra Schrenk
- , Lindsay J. Bischoff
- & Elisa Boscolo
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GSDME-mediated pyroptosis promotes the progression and associated inflammation of atherosclerosis
Macrophages have been shown to have an important function in atherosclerosis. Here the authors show that, in human atherosclerotic plaques and mouse models, GSDME and pyroptosis promote atherosclerosis and inhibition of these pathways could reduce pathology associated with atherosclerotic disease.
- Yuanyuan Wei
- , Beidi Lan
- & Yue Wu
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Molecularly self‐fueled nano-penetrator for nonpharmaceutical treatment of thrombosis and ischemic stroke
Thrombotic cerebro-cardiovascular diseases are the leading causes of disability and death worldwide but current drug therapeutics show important limitations. Here, the authors exploit a selfpropelling nano-penetrator with high fuel loading and controllable motion which is molecularly co-assembled using a photothermal photosensitizer and a photothermal-activable NO donor.
- Hongyuan Zhang
- , Zhiqiang Zhao
- & Cong Luo
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| Open Access
GPR174 knockdown enhances blood flow recovery in hindlimb ischemia mice model by upregulating AREG expression
Gpr174 is a regulator of regulatory T cells, which play an important role in angiogenesis after hindlimb ischemia. Here, the authors show GPR174-deficient Tregs promote AREG expression by inhibiting Gαs/cAMP/PKA signal pathway and increasing EGR1 nuclear accumulation to improve angiogenesis and vascular remodeling in response to ischemic injury.
- Jin Liu
- , Lihong Pan
- & Aijun Sun
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Article
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Extracellular traps from activated vascular smooth muscle cells drive the progression of atherosclerosis
Vascular smooth muscle cells (VSMCs) are known for their fate plasticity in atherosclerosis plaque progression. Here, Zhai et al. show that extracellular traps generated from CD68 + VSMCs adversely contribute to plaque progression and highlight their unexpected role in plaque stability by regulating the direction of VSMC trans-differentiation.
- Ming Zhai
- , Shiyu Gong
- & Wenhui Peng
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Thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom
Population-based studies can provide information on the safety of COVID-19 vaccines. Here the authors report the rates thrombosis and thrombocytopenia after vaccination against and infection with SARS-CoV-2 in the United Kingdom and compare them with the background (expected) rates in the general population.
- Edward Burn
- , Xintong Li
- & Daniel Prieto-Alhambra
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Functionally integrating nanoparticles alleviate deep vein thrombosis in pregnancy and rescue intrauterine growth restriction
There is still an unmet need for effective and safe drugs to treat deep vein thrombosis during pregnancy, a life-threatening condition for the mother and fetus. Here, the authors show that engineered multifunctional nanoparticles can site-specifically dissolve thrombi and reverse deep vein thrombosis-mediated intrauterine growth restriction and delayed development of fetuses in pregnant rats.
- Juan Cheng
- , Siqi Zhang
- & Jianxiang Zhang
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Article
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2′–5′ oligoadenylate synthetase‑like 1 (OASL1) protects against atherosclerosis by maintaining endothelial nitric oxide synthase mRNA stability
Maintaining optimal eNOS levels is important during cardiovascular events, although little is known regarding the mechanism of eNOS protection. Here, the authors show a regulatory role of endothelial OASL1 in maintaining eNOS mRNA stability and vascular biology under atheroprone conditions.
- Tae Kyeong Kim
- , Sejin Jeon
- & Goo Taeg Oh
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von Willebrand factor links primary hemostasis to innate immunity
von Willebrand factor (VWF) plays a critical role in primary hemostasis following vascular injury by tethering platelets to exposed collagen. Here, VWF binding to macrophages is shown to trigger NF-κB activation and induce pro-inflammatory responses.
- Clive Drakeford
- , Sonia Aguila
- & James S. O’Donnell
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Article
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Small molecule-assisted assembly of multifunctional ceria nanozymes for synergistic treatment of atherosclerosis
Regulating reactive oxygen species and inflammation are important for treating atherosclerosis. Here, the authors create a cell membrane coated zoledronic acid ceria nanocomposite loaded with probucol for synergistic drug and scavenging nanozyme treatment of atherosclerosis demonstrating application in vivo.
- Xiaoxue Fu
- , Xiaojuan Yu
- & Chao Yu
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Article
| Open Access
Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling
Perivascular adipose tissue (PVAT) has been reported to undergo inflammatory changes in response to vascular injury. Here, the authors show that vascular injury induces the beiging (brown adipose tissue-like phenotype change) of PVAT, which fine-tunes inflammatory response as a protective mechanism.
- Yusuke Adachi
- , Kazutaka Ueda
- & Issei Komuro
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T cell cholesterol efflux suppresses apoptosis and senescence and increases atherosclerosis in middle aged mice
Cholesterol efflux is mediated by specific transporters in T cells. Here the authors show that when the ABCA1/ABCG1 cholesterol transporters are absent, peripheral T cell numbers are reduced but activation increased with a premature aging phenotype of T cell senescence and apoptosis in middle aged Ldlr−/− mice.
- Venetia Bazioti
- , Anouk M. La Rose
- & Marit Westerterp
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Genome-wide association analysis and replication in 810,625 individuals with varicose veins
Although varicose veins are a common condition, the genetic basis is not well understood. Here, the authors find genetic variants associated with varicose veins and show that a higher polygenic risk score for varicose veins correlates with a greater likelihood of patients undergoing surgical treatment.
- Waheed-Ul-Rahman Ahmed
- , Sam Kleeman
- & Dominic Furniss
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Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
Pulmonary hypertension is a fatal disease that causes right heart failure due to pulmonary artery stenosis. Here, the authors find that ω-3 epoxides produced by the phospholipase PAF-AH2 in mast cells regulate pulmonary vascular remodeling.
- Hidenori Moriyama
- , Jin Endo
- & Motoaki Sano
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Crystal structures of BMPRII extracellular domain in binary and ternary receptor complexes with BMP10
Mutations in BMPR2 is the major genetic cause for pulmonary arterial hypertension (PAH). Here by solving crystal structures of BMPRII in binary and ternary receptor complexes with BMP10, the authors report the molecular recognition between BMPRII and BMP10, and its implication in PAH.
- Jingxu Guo
- , Bin Liu
- & Wei Li
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Article
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ACKR3 regulates platelet activation and ischemia-reperfusion tissue injury
ACKR3 is a critical regulator of platelet-mediated thrombosis and organ injury following ischemia/reperfusion. Platelet ACKR3 surface expression is independently associated with all-cause mortality in patients with cardiovascular diseases.
- Anne-Katrin Rohlfing
- , Kyra Kolb
- & Meinrad Gawaz
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Microskeletal stiffness promotes aortic aneurysm by sustaining pathological vascular smooth muscle cell mechanosensation via Piezo1
Mechanobiological signals have been reported to contribute to abdominal aortic aneurysm (AAA) development. Here the authors report that the microskeletal stiffness and a Piezo1-mediated mechanism influence vascular smooth muscle cell mechanosensation and AAA disease development.
- Weiyi Qian
- , Tarik Hadi
- & Weiqiang Chen
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Article
| Open Access
C-type lectin receptor CLEC4A2 promotes tissue adaptation of macrophages and protects against atherosclerosis
The contribution of distinct subsets of macrophages to atherosclerosis is poorly understood. Here the authors describe a protective subset of vascular macrophages expressing the C-type lectin receptor CLEC4A2, which licenses monocytes to join the resident vascular macrophage pool and ensures vascular homeostasis.
- Inhye Park
- , Michael E. Goddard
- & Claudia Monaco
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Article
| Open Access
Identification of the factor XII contact activation site enables sensitive coagulation diagnostics
Blood coagulation is started by contact to surfaces and this is the principle for a commonly used diagnostic clotting test, aPTT. Here, the authors identify the structure in coagulation factor XII that initiates surface-driven coagulation and use the information to develop improved aPTT assays.
- Marco Heestermans
- , Clément Naudin
- & Thomas Renné
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Article
| Open Access
S-nitrosylation-mediated coupling of G-protein alpha-2 with CXCR5 induces Hippo/YAP-dependent diabetes-accelerated atherosclerosis
S-nitrosylation can influence many pathophysiological processes. Here the authors show that the coupling efficiency of GNAI2 with CXCR5 is enhanced by S-nitrosylation of GNAI2, leading to Hippo-YAP dysfunction in endothelium, and plays a role in diabetes-accelerated atherosclerosis.
- Meng-Lin Chao
- , Shanshan Luo
- & Yong Ji
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Article
| Open Access
Self-healing polyurethane-elastomer with mechanical tunability for multiple biomedical applications in vivo
The unique properties of self-healing materials hold great potential in the field of biomedical engineering. Here, the authors designed a series of biodegradable and biocompatible self-healing elastomers with tunable mechanical properties, and apply them to various disease models in vivo, including aortic aneurism, bone fracture and nerve amputation.
- Chenyu Jiang
- , Luzhi Zhang
- & Xiaofeng Ye
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Article
| Open Access
Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease
Previous studies have shown that the CD40L-CD40 signaling axis plays a role in atherosclerosis. Here the authors investigate the cell-specific functions of the most relevant CD40L-expressing cell types in atherosclerosis. Deficiency of T cell-derived CD40L reduces and stabilizes plaques through impaired Th1 polarization while platelet-derived CD40L ameliorates atherothrombosis.
- Michael Lacy
- , Christina Bürger
- & Esther Lutgens
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Article
| Open Access
OPG/TRAIL ratio as a predictive biomarker of mortality in patients with type A acute aortic dissection
Despite many therapeutic improvements, mortality risk in patients with type A acute aortic dissection remains high. Here the authors construct a biomarker-guided risk stratification tool to predict death, which could potentially contribute to treatment decision-making and improvement of the prognosis.
- Jie Lu
- , Ping Li
- & Yulin Li
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Article
| Open Access
Aortic disease in Marfan syndrome is caused by overactivation of sGC-PRKG signaling by NO
Aortic aneurysm and dissection, the major problem linked to Marfan syndrome (MFS), lacks effective pharmacological treatment. Here, the authors show that the NO pathway is overactivated in MFS and that inhibition of guanylate cyclase and cGMP-dependent protein kinase reverts MFS aortopathy in mice.
- Andrea de la Fuente-Alonso
- , Marta Toral
- & Juan Miguel Redondo
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Article
| Open Access
An endothelial activin A-bone morphogenetic protein receptor type 2 link is overdriven in pulmonary hypertension
Pulmonary arterial hypertension is a progressive fatal disease characterized by pathological pulmonary artery remodeling. Here the authors show that the dysregulation of the activin A-bone morphogenetic protein receptor type 2 link in the endothelium is involved in the progression of pulmonary hypertension.
- Gusty R. T. Ryanto
- , Koji Ikeda
- & Noriaki Emoto
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| Open Access
Caveolae-mediated Tie2 signaling contributes to CCM pathogenesis in a brain endothelial cell-specific Pdcd10-deficient mouse model
Animal models that fully recapitulate human CCM pathogenesis are not currently available. Here, the authors establish a novel CCM model and reveal that caveolae-Tie2 signaling is involved in CCMs formation at the level of venules, which is accompanied by gradual dissociation of pericytes.
- Huanjiao Jenny Zhou
- , Lingfeng Qin
- & Wang Min
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Article
| Open Access
Prevention of CaCl2-induced aortic inflammation and subsequent aneurysm formation by the CCL3–CCR5 axis
Inflammatory cytokines and chemokines are involved in the development of abdominal aortic aneurysm (AAA). Here the authors show that CCL3 prevents the development of CaCl2-induced AAA by suppressing MMP-9 expression.
- Yuko Ishida
- , Yumi Kuninaka
- & Toshikazu Kondo
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Article
| Open Access
AKAP5 complex facilitates purinergic modulation of vascular L-type Ca2+ channel CaV1.2
Molecular mechanisms by which glucose modulates L-type Ca2+ channel activity and vascular reactivity are unclear. Here the authors report a nanocomplex orchestrated by AKAP5 that facilitates local purinergic stimulation of L-type Ca2+ channels and vasoconstriction during diabetic hyperglycemia.
- Maria Paz Prada
- , Arsalan U. Syed
- & Madeline Nieves-Cintrón
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Article
| Open Access
Modeling lung perfusion abnormalities to explain early COVID-19 hypoxemia
Early stages of the novel coronavirus disease (COVID-19) have been associated with silent hypoxia and poor oxygenation despite relatively small fractions of afflicted lung. Here, the authors present a mathematical model which reproduces the vascular pulmonary mechanisms observed in patients with early COVID-19.
- Jacob Herrmann
- , Vitor Mori
- & Béla Suki
LncRNA-LncDACH1 mediated phenotypic switching of smooth muscle cells during neointimal hyperplasia in male arteriovenous fistulas