Arteriosclerosis, Thrombosis, and Vascular Biology

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ISSN / EISSN : 1079-5642 / 1524-4636
Total articles ≅ 12,435
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Lan Huang, Colette Bichsel, Alexis Norris, Jeremy Thorpe, Jonathan Pevsner, , Anna Pinto, David Zurakowski, Robin J. Kleiman, , et al.
Arteriosclerosis, Thrombosis, and Vascular Biology; https://doi.org/10.1161/atvbaha.121.316651

Abstract:
Objective: Capillary malformation (CM) occurs sporadically and is associated with Sturge-Weber syndrome. The somatic mosaic mutation in GNAQ (c.548G>A, p.R183Q) is enriched in endothelial cells (ECs) in skin CM and Sturge-Weber syndrome brain CM. Our goal was to investigate how the mutant Gαq (G-protein αq subunit) alters EC signaling and disrupts capillary morphogenesis. Approach and Results: We used lentiviral constructs to express p.R183Q or wild-type GNAQ in normal human endothelial colony forming cells (EC-R183Q and EC-WT, respectively). EC-R183Q constitutively activated PLC (phospholipase C) β3, a downstream effector of Gαq. Activated PLCβ3 was also detected in human CM tissue sections. Bulk RNA sequencing analyses of mutant versus wild-type EC indicated constitutive activation of PKC (protein kinase C), NF-κB (nuclear factor kappa B) and calcineurin signaling in EC-R183Q. Increased expression of downstream targets in these pathways, ANGPT2 (angiopoietin-2) and DSCR (Down syndrome critical region protein) 1.4 were confirmed by qPCR and immunostaining of human CM tissue sections. The Gαq inhibitor YM-254890 as well as siRNA targeted to PLCβ3 reduced mRNA expression levels of these targets in EC-R183Q while the pan-PKC inhibitor AEB071 reduced ANGPT2 but not DSCR1.4. EC-R183Q formed enlarged blood vessels in mice, reminiscent of those found in human CM. shRNA knockdown of ANGPT2 in EC-R183Q normalized the enlarged vessels to sizes comparable those formed by EC-WT. Conclusions: Gαq-R183Q, when expressed in ECs, establishes constitutively active PLCβ3 signaling that leads to increased ANGPT2 and a proangiogenic, proinflammatory phenotype. EC-R183Q are sufficient to form enlarged CM-like vessels in mice, and suppression of ANGPT2 prevents the enlargement. Our study provides the first evidence that endothelial Gαq-R183Q is causative for CM and identifies ANGPT2 as a contributor to CM vascular phenotype.
Yutaka Matsubara, Luis Gonzalez, Gathe Kiwan, Jia Liu, , Mingjie Gao, Xixiang Gao, Ryosuke Taniguchi, Bogdan Yatsula, Tadashi Furuyama, et al.
Arteriosclerosis, Thrombosis, and Vascular Biology; https://doi.org/10.1161/atvbaha.121.316380

Abstract:
Objective: Patients with end-stage renal disease depend on hemodialysis for survival. Although arteriovenous fistulae (AVF) are the preferred vascular access for hemodialysis, the primary success rate of AVF is only 30% to 50% within 6 months, showing an urgent need for improvement. PD-L1 (programmed death ligand 1) is a ligand that regulates T-cell activity. Since T cells have an important role during AVF maturation, we hypothesized that PD-L1 regulates T cells to control venous remodeling that occurs during AVF maturation. Approach and results: In the mouse aortocaval fistula model, anti-PD-L1 antibody (200 mg, 3×/wk intraperitoneal) was given to inhibit PD-L1 activity during AVF maturation. Inhibition of PD-L1 increased T-helper type 1 cells and T-helper type 2 cells but reduced regulatory T cells to increase M1-type macrophages and reduce M2-type macrophages; these changes were associated with reduced vascular wall thickening and reduced AVF patency. Inhibition of PD-L1 also inhibited smooth muscle cell proliferation and increased endothelial dysfunction. The effects of anti-PD-L1 antibody on adaptive venous remodeling were diminished in nude mice; however, they were restored after T-cell transfer into nude mice, indicating the effects of anti-PD-L1 antibody on venous remodeling were dependent on T cells. Conclusions: Regulation of PD-L1 activity may be a potential therapeutic target for clinical translation to improve AVF maturation.
Xiaohan Mei, Xiao-Bing Cui, Yiran Li,
Arteriosclerosis, Thrombosis, and Vascular Biology; https://doi.org/10.1161/atvbaha.121.316911

Abstract:
Objective: Vascular smooth muscle cell (SMC) proliferation contributes to neointima formation following vascular injury. Circular RNA—a novel type of noncoding RNA with closed-loop structure—exhibits cell- and tissue-specific expression patterns. However, the role of circular RNA in SMC proliferation and neointima formation is largely unknown. The objective of this study is to investigate the role and mechanism of circSOD2 in SMC proliferation and neointima formation. Approach and Results: Circular RNA profiling of human aortic SMCs revealed that PDGF (platelet-derived growth factor)-BB up- and downregulated numerous circular RNAs. Among them, circSOD2, derived from back-splicing event of SOD2 (superoxide dismutase 2), was significantly enriched. Knockdown of circSOD2 by short hairpin RNA blocked PDGF-BB–induced SMC proliferation. Inversely, circSOD2 ectopic expression promoted SMC proliferation. Mechanistically, circSOD2 acted as a sponge for miR-206, leading to upregulation of NOTCH3 and NOTCH3 signaling, which regulates cyclin D1 and CDK (cyclin-dependent kinase) 4/6. In vivo studies showed that circSOD2 was induced in neointima SMCs in balloon-injured rat carotid arteries. Importantly, knockdown of circSOD2 attenuated injury-induced neointima formation along with decreased neointimal SMC proliferation. Conclusions: CircSOD2 is a novel regulator mediating SMC proliferation and neointima formation following vascular injury. Therefore, circSOD2 could be a potential therapeutic target for inhibiting the development of proliferative vascular diseases.
Lingfeng Qin, Haifeng Zhang, Busu Li, Quan Jiang, , ,
Arteriosclerosis, Thrombosis, and Vascular Biology; https://doi.org/10.1161/atvbaha.121.316707

Abstract:
Objective: Cerebral cavernous malformations (CCMs) can happen anywhere in the body, although they most commonly produce symptoms in the brain. The role of CCM genes in other vascular beds outside the brain and retina is not well-examined, although the 3 CCM-associated genes ( CCM1 , CCM2 , and CCM3 ) are ubiquitously expressed in all tissues. We aimed to determine the role of CCM gene in lymphatics. Approach and Results: Mice with an inducible pan–endothelial cell (EC) or lymphatic EC deletion of Ccm3 ( Pdcd10 ECKO or Pdcd10 LECKO ) exhibit dilated lymphatic capillaries and collecting vessels with abnormal valve structure. Morphological alterations were correlated with lymphatic dysfunction in Pdcd10 LECKO mice as determined by Evans blue dye and fluorescein isothiocyanate(FITC)-dextran transport assays. Pdcd10 LECKO lymphatics had increased VEGFR3 (vascular endothelial growth factor receptor-3)-ERK1/2 signaling with lymphatic hyperplasia. Mechanistic studies suggested that VEGFR3 is primarily regulated at a transcriptional level in Ccm3-deficient lymphatic ECs, in an NF-κB (nuclear factor κB)–dependent manner. CCM3 binds to importin alpha 2/KPNA2 (karyopherin subunit alpha 2), and a CCM3 deletion releases KPNA2 to activate NF-κB P65 by facilitating its nuclear translocation and P65-dependent VEGFR3 transcription. Moreover, increased VEGFR3 in lymphatic EC preferentially activates ERK1/2 signaling, which is critical for lymphatic EC proliferation. Importantly, inhibition of VEGFR3 or ERK1/2 rescued the lymphatic defects in structure and function. Conclusions: Our data demonstrate that CCM3 deletion augments the VEGFR3-ERK1/2 signaling in lymphatic EC that drives lymphatic hyperplasia and malformation and warrant further investigation on the potential clinical relevance of lymphatic dysfunction in patients with CCM.
Erik A.L. Biessen, Theo J.C. Van Berkel
Arteriosclerosis, Thrombosis, and Vascular Biology; https://doi.org/10.1161/atvbaha.121.316290

Abstract:
While the promise of oligonucleotide therapeutics, such as (chemically modified) ASO (antisense oligonucleotides) and short interfering RNAs, is undisputed from their introduction onwards, their unfavorable pharmacokinetics and intrinsic capacity to mobilize innate immune responses, were limiting widespread clinical use. However, these major setbacks have been tackled by breakthroughs in chemistry, stability and delivery. When aiming an intervention hepatic targets, such as lipid and sugar metabolism, coagulation, not to mention cancer and virus infection, introduction of N-acetylgalactosamine aided targeting technology has advanced the field profoundly and by now a dozen of N-acetylgalactosamine therapeutics for these indications have been approved for clinical use or have progressed to clinical trial stage 2 to 3 testing. This technology, in combination with major advances in oligonucleotide stability allows safe and durable intervention in targets that were previously deemed undruggable, such as Lp(a) and PCSK9, at high efficacy and specificity, often with as little as 2 doses per year. Their successful use even the most visionary would not have predicted 2 decades ago. Here, we will review the evolution of N-acetylgalactosamine technology. We shall outline their fundamental design principles and merits, and their application for the delivery of oligonucleotide therapeutics to the liver. Finally, we will discuss the perspectives of N-acetylgalactosamine technology and propose directions for future research in receptor targeted delivery of these gene medicines.
Qin Bai, Yao Lu, Yanhua Chen, Han Zhang, Weiwei Zhang, Huang Wu, Aiqing Wen
Arteriosclerosis, Thrombosis, and Vascular Biology; https://doi.org/10.1161/atvbaha.121.316414

Abstract:
Objective: METTL3 (methyltransferase-like protein 3)-mediated N 6 -methyladenosine modification is the most abundant RNA modification on eukaryote mRNAs and plays a crucial role in diverse physiological and pathological processes. However, whether N 6 -methyladenosine modification has function in thrombosis is unknown. This study aims to determine the role of METTL3 in the endothelial cells-mediated thrombosis. Approach and Results: RNA-sequencing and real-time quantitative PCR revealed that the expression of PAI-1 (plasminogen activator inhibitor-1) was downregulated in METTL3 knockdown human umbilical vein endothelial cells. In vitro experiments showed that METTL3 suppressed fibrinolysis. Mechanically, RNA methylation sequencing and meRIP-quantitative real-time PCR showed that METTL3 catalyzed N 6 -methyladenosine modification on 3′ UTR of JUN mRNA. Western blotting analysis showed that METTL3 promoted JUN protein expression. Chromatin immunoprecipitation analysis demonstrated that JUN bound to the PAI-1 promoter in human umbilical vein endothelial cells. Furthermore, mice challenged with lipopolysaccharide resulted in higher METTL3 expression in vessels. Endothelial-specific knockdown of Mettl3 decreased expression of active PAI-1 in plasma and attenuated fibrin deposition in livers and lungs during endotoxemia. Conclusions: Our study reveals that METTL3-mediated N 6 -methyladenosine modification plays a crucial role in fibrinolysis and is an underlying target for the therapy of thrombotic disorders.
Emily M. Nordquist, Punashi Dutta, Karthik M. Kodigepalli, Carol Mattern, Michael R. McDermott, Aaron J. Trask, Stephanie LaHaye, Volkhard Lindner,
Arteriosclerosis, Thrombosis, and Vascular Biology; https://doi.org/10.1161/atvbaha.121.316450

Abstract:
Objective: Aortic valve disease is a common worldwide health burden with limited treatment options. Studies have shown that the valve endothelium is critical for structure-function relationships, and disease is associated with its dysfunction, damage, or injury. Therefore, therapeutic targets to maintain a healthy endothelium or repair damaged endothelial cells could hold promise. In this current study, we utilize a surgical mouse model of heart valve endothelial cell injury to study the short-term response to injury at molecular and cellular levels. The goal is to determine if the native heart valve exhibits a reparative response and identify the mechanisms underlying this process. Approach and Results: Mild aortic valve endothelial injury and abrogated function was evoked by inserting a guidewire down the carotid artery of young (3 months) and aging (16–18 months) wild-type mice. Short-term cellular responses were examined at 6 hours, 48 hours, and 4 weeks following injury, whereas molecular profiles were determined after 48 hours by RNA-sequencing. Within 48 hours following endothelial injury, young wild-type mice restore endothelial barrier function in association with increased cell proliferation, and upregulation of transforming growth factor beta 1 ( Tgfβ1 ) and the glycoprotein, collagen triple helix repeat containing 1 ( Cthrc1 ). Interestingly, this beneficial response to injury was not observed in aging mice with known underlying endothelial dysfunction. Conclusions: Data from this study suggests that the healthy valve has the capacity to respond to mild endothelial injury, which in short term has beneficial effects on restoring endothelial barrier function through acute activation of the Tgfβ1-Cthrc1 signaling axis and cell proliferation.
Gissette Reyes-Soffer, Henry N. Ginsberg, Lars Berglund, P. Barton Duell, Sean P. Heffron, Pia R. Kamstrup, Donald M. Lloyd-Jones, Santica M. Marcovina, Calvin Yeang, Marlys L. Koschinsky
Arteriosclerosis, Thrombosis, and Vascular Biology; https://doi.org/10.1161/atv.0000000000000147

Abstract:
High levels of lipoprotein(a) [Lp(a)], an apoB100-containing lipoprotein, are an independent and causal risk factor for atherosclerotic cardiovascular diseases through mechanisms associated with increased atherogenesis, inflammation, and thrombosis. Lp(a) is predominantly a monogenic cardiovascular risk determinant, with ≈70% to ≥90% of interindividual heterogeneity in levels being genetically determined. The 2 major protein components of Lp(a) particles are apoB100 and apolipoprotein(a). Lp(a) remains a risk factor for cardiovascular disease development even in the setting of effective reduction of plasma low-density lipoprotein cholesterol and apoB100. Despite its demonstrated contribution to atherosclerotic cardiovascular disease burden, we presently lack standardization and harmonization of assays, universal guidelines for diagnosing and providing risk assessment, and targeted treatments to lower Lp(a). There is a clinical need to understand the genetic and biological basis for variation in Lp(a) levels and its relationship to disease in different ancestry groups. This scientific statement capitalizes on the expertise of a diverse basic science and clinical workgroup to highlight the history, biology, pathophysiology, and emerging clinical evidence in the Lp(a) field. Herein, we address key knowledge gaps and future directions required to mitigate the atherosclerotic cardiovascular disease risk attributable to elevated Lp(a) levels.
Arteriosclerosis, Thrombosis, and Vascular Biology; https://doi.org/10.1161/atvbaha.121.315852

Abstract:
The aorta is highly heterogeneous, containing many different types of cells that perform sophisticated functions to maintain aortic homeostasis. Recently, single-cell RNA sequencing studies have provided substantial new insight into the heterogeneity of vascular cell types, the comprehensive molecular features of each cell type, and the phenotypic interrelationship between these cell populations. This new information has significantly improved our understanding of aortic biology and aneurysms at the molecular and cellular level. Here, we summarize these findings, with a focus on what single-cell RNA sequencing analysis has revealed about cellular heterogeneity, cellular transitions, communications among cell populations, and critical transcription factors in the vascular wall. We also review the information learned from single-cell RNA sequencing that has contributed to our understanding of the pathogenesis of vascular disease, such as the identification of cell types in which aneurysm-related genes and genetic variants function. Finally, we discuss the challenges and future directions of single-cell RNA sequencing applications in studies of aortic biology and diseases.
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