Mechano-sensitive TET1s inhibits endothelial athero-susceptible phenotype through regulating YAP phosphorylation

Atherosclerosis is a chronic progressive disease and one of the major causes of cardio-cerebral vascular diseases.Accumulating evidence indicates that endothelial dysfunc-tion is the initiating step in atherosclerosis.The pattern of local blood flow becomes disturbed(low and oscillatory shear stress[OSS])in the curved or branched segments of the arterial tree,causing endothelial cells(ECs)to exhibit athero-susceptible phenotypes,such as hyperproliferation and inflammation.

Desulfovibrio desulfuricans aggravates atherosclerosis by enhancing intestinal permeability and endothelial TLR4/NF-kB pathway in Apoe^(-/-) mice

It is increasingly aware that gut microbiota is closely associated with atherosclerosis.However,which and how specific gut bacteria regulate the progression of atherosclerosis is still poorly understood.In this study,modified linear discriminant analysis was performed in comparing the gut microbiota structures of atherosclerotic and non-atherosclerotic mice,and Desulfovibrio desulfuricans(D.desulfuricans)was found to be associatedwith atherosclerosis.D.desulfuricans-treated Apoe^(-/-) mice showed significantly aggravated atherosclerosis.The proatherogenic effect of D.desulfuricans was attributed to its ability to increase intestinal permeability and subsequent raise in the transit of lipopolysaccharide(LPS)from the intestine to the bloodstream.Excessive LPS in the blood can elicit local and systemic inflammation and activate Toll-like receptor 4(TLR4)/nuclear factor-kB(NF-kB)signaling of endothelial cells.TAK-242,a specific inhibitor of TLR4,can ameliorate the development of D.desulfuricansinduced atherosclerosis by blocking the LPS-induced activation of TLR4/NF-kB signaling.

A novel mechanism of inhibiting in-stent restenosis with arsenic trioxide drug-eluting stent: Enhancing contractile phenotype of vascular smooth muscle cells via YAP pathway

Objective:Arsenic trioxide(ATO or As2O3)has beneficial effects on suppressing neointimal hyperplasia and restenosis,but the mechanism is still unclear.The goal of this study is to further understand the mechanism of ATO's inhibitory effect on vascular smooth muscle cells(VSMCs).Methods and results:Through in vitro cell culture and in vivo stent implanting into the carotid arteries of rabbit,a synthetic-to-contractile phenotypic transition was induced and the proliferation of VSMCs was inhibited by ATO.F-actin filaments were clustered and the elasticity modulus was increased within the phenotypic modulation of VSMCs induced by ATO in vitro.Meanwhile,Yes-associated protein(YAP)nuclear translocation was inhibited by ATO both in vivo and in vitro.It was found that ROCK inhibitor or YAP inactivator could partially mask the phenotype modulation of ATO on VSMCs.Conclusions:The interaction of YAP with the ROCK pathway through ATO seems to mediate the contractile phenotype of VSMCs.This provides an indication of the clinical therapeutic mechanism for the beneficial bioactive effect of ATO-drug eluting stent(AES)on in-stent restenosis(ISR).

High shear stress induces atherosclerotic vulnerable plaque formation through angiogenesis

Rupture of atherosclerotic plaques causing thrombosis is the main cause of acute coronary syndrome and ischemic strokes.Inhibition of thrombosis is one of the important tasks developing biomedical materials such as intravascular stents and vascular grafts.Shear stress(SS)influences the formation and development of atherosclerosis.The current review focuses on the vulnerable plaques observed in the high shear stress(HSS)regions,which localizes at the proximal region of the plaque intruding into the lumen.The vascular outward remodelling occurs in the HSS region for vascular compensation and that angiogenesis is a critical factor for HSS which induces atherosclerotic vulnerable plaque formation.These results greatly challenge the established belief that low shear stress is important for expansive remodelling,which provides a new perspective for preventing the transition of stable plaques to high-risk atherosclerotic lesions.

Effect of intraplaque angiogenesis to atherosclerotic rupture-prone plaque induced by high shear stress in rabbit model

Atherosclerotic prone-rupture plaque is mainly localized in the region of the entrance to the stenosiswith high shear stress and the reasons are largely unknown. Our hypothesis is that such a distributionof cells in atherosclerotic plaque may depend on the angiogenesis. Silastic collars inducedregions of high shear stress (20.6865.27 dynes/cm2) in the upstream flow and low shear stress(12.2561.28 dynes/cm2) in the downstream flow in carotid arteries. Compared with the low shearstress region, plaques in the high shear stress region showed more intraplaque haemorrhaging,less collagen and higher apoptotic rates of vascular smooth muscle cells;endothelial cells (ECs) inthe high shear stress region were characterized with integrity and high endothelial nitric oxidesynthase (eNOS) expression (1570.36345.5% vs 172.9649.9%). The number of intraplaque microvesselsis very high in the high shear stress region (1561.8 n/mm2 vs 3.560.4 n/mm2), and themicrovessels in the plaque show ECs were abnormal, with membrane blebs, intracytoplasmic vacuolesand leukocyte infiltration. Our current study reveals that the integrity of the endothelium andthe vulnerability of atherosclerotic plaques are simultaneously localized in high shear stress regions,and we provide evidence for the first time that microvessels in the intraplaque maybe responsiblefor rupture-prone plaque formation in the high shear stress region.

Uptake of oxidative stress-mediated extracellular vesicles by vascular endothelial cells under low magnitude shear stress

Extracellular vesicles(EVs)are increasingly used as delivery vehicles for drugs and bioactive molecules,which usually require intravascular administration.The endothelial cells covering the inner surface of blood vessels are susceptible to the shear stress of blood flow.Few studies demonstrate the interplay of red blood cell-derived EVs(RBCEVs)and endothelial cells.Thus,the phagocytosis of EVs by vascular endothelial cells during blood flow needs to be elucidated.In this study,red blood cell-derived extracellular vesicles(RBCEVs)were constructed to investigate endothelial cell phagocytosis in vitro and animal models.Results showed that low magnitude shear stress including low shear stress(LSS)and oscillatory shear stress(OSS)could promote the uptake of RBCEVs by endothelial cells in vitro.In addition,in zebrafish and mouse models,RBCEVs tend to be internalized by endothelial cells under LSS or OSS.Moreover,RBCEVs are easily engulfed by endothelial cells in atherosclerotic plaques exposed to LSS or OSS.In terms of mechanism,oxidative stress induced by LSS is part of the reason for the increased uptake of endothelial cells.Overall,this study shows that vascular endothelial cells can easily engulf EVs in areas of low magnitude shear stress,which will provide a theoretical basis for the development and utilization of EVs-based nano-drug delivery systems in vivo.

G3BP2 regulates oscillatory shear stress-induced endothelial dysfunction

GTPase-activating SH3 domain-binding protein 2(G3BP2)is a mediator that responds to environmental stresses through stress granule formation and is involved in the progression of chronic diseases.However,no studies have examined the contribution of G3BP2 in the oscillatory shear stress(OSS)-induced endothelial dysfunction.Here we assessed the effects of G3BP2 in endothelial cells(ECs)function and investigated the underlying mechanism.Using shear stress apparatus and partial ligation model,we identified that stress granulerelated genes in ECs could be induced by OSS with RNA-seq,and then confirmed that G3BP2 was highly and specifically expressed in athero-susceptible endothelia in the OSS regions.G3bp2e/eApoee/e mice had significantly decreased atherosclerotic lesions associated with deficiency of G3BP2 in protecting endothelial barrier function,decreasing monocyte adhesion to ECs and inhibiting the proinflammatory cytokine levels.Furthermore,loss of G3BP2 diminished OSS-induced inflammation in ECs by increasing YAP nucleocytoplasmic shuttling and phosphorylation.These data demonstrate that G3BP2 is a critical OSS regulated gene in regulating ECs function and that G3BP2 inhibition in ECs is a promising atheroprotective therapeutic strategy.

trans-2-Enoyl-CoA Reductase Tecr-Driven Lipid Metabolism in Endothelial Cells Protects against Transcytosis to Maintain Blood-Brain Barrier Homeostasis

The transport and metabolism of lipids in cerebrovascular endothelial cells(ECs)have been hypothesized to regulate blood-brain barrier(BBB)maturation and homeostasis.Long-chain polyunsaturated fatty acids(LCPUFAs)as the important lipids components of cell membranes are essential for the development and function of BBB,but the direct links of lipid metabolism and ECs barrier function remain to be established.Here,we comprehensively characterize the transcriptomic phenotype of developmental cerebrovascular ECs in single-cell resolution and firstly find that trans-2-enoyl-CoA reductase(Tecr),a verylong-chain fatty acid synthesis,is highly expressed during barriergenesis and decreased after BBB maturation.EC-specific knockout of Tecr compromises angiogenesis due to delayed vascular sprouting.Importantly,EC-specific deletion of Tecr loss restrictive quality of vascular permeability from neonatal stages to adulthood,with high levels of transcytosis,but maintains the vascular tight junctions.Moreover,lipidomic analysis shows that the expression of Tecr in ECs is associated with the containing of omega-3 fatty acids,which directly suppresses caveolae vesicles formation.These results reveal a protective role for Tecr in BBB integrity and suggest that Tecr as a novel therapeutic target in the central nervous system(CNS)diseases associated with BBB dysfunction.

Corrigendum to“A novel mechanism of inhibiting in-stent restenosis with arsenic trioxide drug-eluting stent:Enhancing contractile phenotype of vascular smooth muscle cells via YAP pathway”[Bioact.Mater.62(February 2021)375-385]

The authors regret the publication of incorrect fund numbers in the acknowledgment section of the article.The number“cstc2019jcyj-zdxm0033”has been updated as“cstc2019jcyj-zdxmX0028”.The corrected acknowledgment section is as follows:This study was supported in part by grants from the National Natural Science Foundation,China(31971242,31701275),the Natural Science Foundation of Chongqing,China(cstc2020jcjy-msxmX0189),the Chongqing Research Program of Basic Research and Frontier Technology,China(cstc2019jcjy-dxmX0028),Open Fund for Key Laboratory of Biorheological Science and Technology,Ministry of Education,China(CQKLBST-2019-010),Innovation Talent Project of 2020 for Chongqing Primary and secondary School,China(CY200405)and the National Key R&D Program,China(2016YFC1102305).The support from the Chongqing Engineering Laboratory in Vascular Implants,China,the Public Experiment Centre of State Bioindustrial Base(Chongqing)and the National“111 Plan”,China(B06023)are gratefully acknowledged.

Alterations in gut microbiota and physiological factors associated with abdominal aortic aneurysm

Abdominal aortic aneurysm(AAA)is a progressive focal dilatation and weakening of the abdominal aorta,causing 1.3%of all deaths among men aged 65–85 years worldwide.The formation of AAA is a complex process with multiple risk factors.Therefore,this study aimed to determine the relationship of disease severity and physiological factors,and gut microbiota structures in AAA patients.Physiological indicators and fecal 16S rRNA gene sequences from healthy controls and patients with AAA were collected.The correlations between the diameter of the AAA and clinical parameters,and gut microbiota composition were then analyzed separately using multivariable analysis.The diameter of AAA was extremely positively correlated with smoking index,alkaline phosphatase,blood glucose,and blood triglycerides and negatively correlated with prealbumin and Cystatin C.As the diameter of AAA increased,the α-diversity,including Chao 1,Shannon,and Simpson indices,of the gut microbiota decreased and presented a negative linear relationship.Patients with AAA with more severe disease had significantly increased relative abundance of Enterobacteriaceae and decreased relative abundance of Veillonellaceae.A strong correlation was observed between the diameter and physiological data,as well as between diameter and gut microbiota composition.This study could improve the understanding of AAA,and gut microbiota may be a potential target to prevent and treat this deadly disease.

Effects of COVID-19 pandemic on human fertility:A scientometric and visualized evaluation

CovID-19,also known as coronavirus disease 2019,is a novel coronavirus disease with high infectivity,strong heterogeneity,and long incubation period(generally 3-14 days).Its main symptoms and signs include fever,dry cough,nasal congestion,fatigue,disorientation,lymphopenia,and dyspnea.The short-term and long-term impacts of covID-19 on human health,particularly its effects on human reproduction and offspring development,continue to receive significant concerns,as they may lead to potential sequelae for several decades or even centuries.