Genomic Characterization of Endothelial Enhancers Reveals a Multifunctional Role for NR2F2 in Regulation of Arteriovenous Gene Expression.

Abstract:

RATIONALE:Significant progress has revealed transcriptional inputs that underlie regulation of artery and vein endothelial cell fates. However, little is known concerning genome-wide regulation of this process. Therefore, such studies are warranted to address this gap. OBJECTIVE:To identify and characterize artery- and vein-specific endothelial enhancers in the human genome, thereby gaining insights into mechanisms by which blood vessel identity is regulated. METHODS AND RESULTS:Using chromatin immunoprecipitation and deep sequencing for markers of active chromatin in human arterial and venous endothelial cells, we identified several thousand artery- and vein-specific regulatory elements. Computational analysis revealed that NR2F2 (nuclear receptor subfamily 2, group F, member 2) sites were overrepresented in vein-specific enhancers, suggesting a direct role in promoting vein identity. Subsequent integration of chromatin immunoprecipitation and deep sequencing data sets with RNA sequencing revealed that NR2F2 regulated 3 distinct aspects related to arteriovenous identity. First, consistent with previous genetic observations, NR2F2 directly activated enhancer elements flanking cell cycle genes to drive their expression. Second, NR2F2 was essential to directly activate vein-specific enhancers and their associated genes. Our genomic approach further revealed that NR2F2 acts with ERG (ETS-related gene) at many of these sites to drive vein-specific gene expression. Finally, NR2F2 directly repressed only a small number of artery enhancers in venous cells to prevent their activation, including a distal element upstream of the artery-specific transcription factor, HEY2 (hes related family bHLH transcription factor with YRPW motif 2). In arterial endothelial cells, this enhancer was normally bound by ERG, which was also required for arterial HEY2 expression. By contrast, in venous endothelial cells, NR2F2 was bound to this site, together with ERG, and prevented its activation. CONCLUSIONS:By leveraging a genome-wide approach, we revealed mechanistic insights into how NR2F2 functions in multiple roles to maintain venous identity. Importantly, characterization of its role at a crucial artery enhancer upstream of HEY2 established a novel mechanism by which artery-specific expression can be achieved.

journal_name

Circ Res

journal_title

Circulation research

authors

Sissaoui S,Yu J,Yan A,Li R,Yukselen O,Kucukural A,Zhu LJ,Lawson ND

doi

10.1161/CIRCRESAHA.119.316075

subject

Has Abstract

pub_date

2020-03-27 00:00:00

pages

875-888

issue

7

eissn

0009-7330

issn

1524-4571

journal_volume

126

pub_type

杂志文章
  • Possible mechanisms of ventricular arrhythmias elicited by ischemia followed by reperfusion. Studies on isolated canine ventricular tissues.

    abstract::The purpose of this study was to develop an isolated tissue model in which arrhythmic activity could be generated in response to conditions encountered in ischemia followed by reperfusion, and in which intracellular recordings could be used to identify and study arrhythmogenic mechanisms. Isolated canine Purkinje fibe...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.56.2.184

    authors: Ferrier GR,Moffat MP,Lukas A

    更新日期:1985-02-01 00:00:00

  • Hypoxia-induced endothelial apoptosis through nuclear factor-kappaB (NF-kappaB)-mediated bcl-2 suppression: in vivo evidence of the importance of NF-kappaB in endothelial cell regulation.

    abstract::The transcription factor nuclear factor-kappaB (NF-kappaB) plays a pivotal role in the coordinated transactivation of cytokine and adhesion molecule genes involved in endothelial activation. Although recent reports have documented the contribution of NF-kappaB to apoptosis, it is still controversial. Especially, the r...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.86.9.974

    authors: Matsushita H,Morishita R,Nata T,Aoki M,Nakagami H,Taniyama Y,Yamamoto K,Higaki J,Yasufumi K,Ogihara T

    更新日期:2000-05-12 00:00:00

  • Combined inhibition of endothelin and angiotensin II receptors blocks volume load-induced cardiac hormone release.

    abstract::Volume expansion has been shown to increase plasma atrial natriuretic peptide (ANP) levels, but the precise role of paracrine and autocrine factors in stretch-induced cardiac hormone release is not clear. In the present study, we report the effects of endothelin (ET) and angiotensin receptor (AT receptor) antagonists ...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.80.1.114

    authors: Leskinen H,Vuolteenaho O,Ruskoaho H

    更新日期:1997-01-01 00:00:00

  • Enhanced Na(+)-Ca2+ exchange in the infarcted heart. Implications for excitation-contraction coupling.

    abstract::Cellular Ca2+ regulation is abnormal in diseased hearts. We designed this study to assess the role of the Na(+)-Ca2+ exchanger in excitation-contraction coupling in surviving myocardium of the infarcted heart. We measured cellular contractions and whole-cell currents in single left ventricular myocytes isolated from t...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.81.6.1083

    authors: Litwin SE,Bridge JH

    更新日期:1997-12-01 00:00:00

  • Endothelium-specific in vivo gene transfer.

    abstract::Targeted expression of genetic material within the vascular endothelium is potentially a powerful tool for the investigation of endothelial cell (EC) biology. We developed, optimized, and characterized an efficient somatic transgenic model of EC-specific gene transfer. Rat carotid arteries were infused with adenovirus...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.77.3.475

    authors: Schulick AH,Dong G,Newman KD,Virmani R,Dichek DA

    更新日期:1995-09-01 00:00:00

  • Defect in microvascular adaptation to chronic changes in blood flow in mice lacking the gene encoding for dystrophin.

    abstract::Dystrophin has a key role in striated muscle mechanotransduction. In mice lacking the gene encoding for dystrophin (mdx mice), the absence of dystrophin and several other proteins of the dystrophin-glycoprotein complex induces a defect in flow (shear stress)-mediated NO-dependent dilation (FMD). Because the endotheliu...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.0000047505.11002.81

    authors: Loufrani L,Levy BI,Henrion D

    更新日期:2002-12-13 00:00:00

  • Functional Recovery of a Human Neonatal Heart After Severe Myocardial Infarction.

    abstract:RATIONALE:Cardiac remodeling and subsequent heart failure remain critical issues after myocardial infarction despite improved treatment and reperfusion strategies. Recently, cardiac regeneration has been demonstrated in fish and newborn mice after apex resection or cardiac infarctions. Two key issues remain to translat...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.115.307017

    authors: Haubner BJ,Schneider J,Schweigmann U,Schuetz T,Dichtl W,Velik-Salchner C,Stein JI,Penninger JM

    更新日期:2016-01-22 00:00:00

  • Species-specific differences in positive and negative regulatory elements in the renin gene enhancer.

    abstract::A distal transcriptional enhancer has been previously reported upstream of the mouse renin gene. A homologous sequence is also present upstream of the human renin gene, but the mouse and human renin enhancers differ markedly in their ability to activate transcription of a renin promoter. Although the 2 enhancers share...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.85.6.479

    authors: Shi Q,Black TA,Gross KW,Sigmund CD

    更新日期:1999-09-17 00:00:00

  • Mechanism of sustained mechanical alternans. Effect of variations in ventricular billing volume.

    abstract::This study investigations the phenomenon of sustained mechanical alternans (SMA) through the use of quantitative criteria. Discrete analysis is used to demonstrate that the hemodynamic variables during SMA are governed by a simple mathematical relation. The analysis shows that the value of the slope created by the two...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.69.1.26

    authors: Adler D,Nikolic S,Sonnenblick EH,Yellin EL

    更新日期:1991-07-01 00:00:00

  • Adenosine A1 stimulation activates delta-protein kinase C in rat ventricular myocytes.

    abstract::By making use of immunoblotting and immunocytochemical analysis, we explored whether stimulation of adenosine A1 receptors would promote the activation of delta-protein kinase C (delta-PKC) immunolabeled with a polyclonal antibody. Immunoblot analysis of Triton X-100-soluble cell membrane and cytosolic fractions revea...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.78.1.161

    authors: Henry P,Demolombe S,Pucéat M,Escande D

    更新日期:1996-01-01 00:00:00

  • Cardiac energy metabolism in obesity.

    abstract::Obesity results in marked alterations in cardiac energy metabolism, with a prominent effect being an increase in fatty acid uptake and oxidation by the heart. Obesity also results in dramatic changes in the release of adipokines, such as leptin and adiponectin, both of which have emerged as important regulators of car...

    journal_title:Circulation research

    pub_type: 杂志文章,评审

    doi:10.1161/CIRCRESAHA.107.150417

    authors: Lopaschuk GD,Folmes CD,Stanley WC

    更新日期:2007-08-17 00:00:00

  • Reduced reperfusion-induced Ins(1,4,5)P3 generation and arrhythmias in hearts expressing constitutively active alpha1B-adrenergic receptors.

    abstract::Reperfusion of globally ischemic rat hearts causes the generation of inositol(1,4,5)trisphosphate [Ins(1,4,5)P3] and the initiation of arrhythmias. These responses are mediated by alpha1-adrenergic receptors (ARs), but the subtype of receptor involved has not been identified. Under normoxic conditions, hearts from tra...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.83.12.1232

    authors: Harrison SN,Autelitano DJ,Wang BH,Milano C,Du XJ,Woodcock EA

    更新日期:1998-12-14 00:00:00

  • Effect of sulfinpyrazone on homocysteine-induced endothelial injury and arteriosclerosis in baboons.

    abstract::The effect of sulfinpyrazone on endothelial injury induced by homocysteine has been studied both in vitro, using cultured human umbilical vein endothelial cells, and in vivo, using a primate model of homocysteine-induced arteriosclerosis. Oral sulfinpyrazone (250 mumol/kg body weight per day in three divided doses) in...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.53.6.731

    authors: Harker LA,Harlan JM,Ross R

    更新日期:1983-12-01 00:00:00

  • Effects of increasing intercellular resistance on transverse and longitudinal propagation in sheep epicardial muscle.

    abstract::Propagation in cardiac muscle is faster in the longitudinal than in the transverse axis of the cells. Yet, as a result of the larger upstroke velocity of action potentials propagating transversely, it has been suggested that longitudinal propagation is more vulnerable to block. To study the relation between conduction...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.60.5.780

    authors: Delmar M,Michaels DC,Johnson T,Jalife J

    更新日期:1987-05-01 00:00:00

  • Cardiac-specific YAP activation improves cardiac function and survival in an experimental murine MI model.

    abstract:RATIONALE:Yes-associated protein (YAP), the terminal effector of the Hippo signaling pathway, is crucial for regulating embryonic cardiomyocyte proliferation. OBJECTIVE:We hypothesized that YAP activation after myocardial infarction (MI) would preserve cardiac function and improve survival. METHODS AND RESULTS:We use...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.115.303632

    authors: Lin Z,von Gise A,Zhou P,Gu F,Ma Q,Jiang J,Yau AL,Buck JN,Gouin KA,van Gorp PR,Zhou B,Chen J,Seidman JG,Wang DZ,Pu WT

    更新日期:2014-07-18 00:00:00

  • Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo.

    abstract::Therapeutic angiogenesis using vascular endothelial growth factor (VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for improved vascularization,...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.RES.0000133247.69803.c3

    authors: van Weel V,Deckers MM,Grimbergen JM,van Leuven KJ,Lardenoye JH,Schlingemann RO,van Nieuw Amerongen GP,van Bockel JH,van Hinsbergh VW,Quax PH

    更新日期:2004-07-09 00:00:00

  • Hemodynamic effects of diltiazem in hypertension.

    abstract::Cardiac hemodynamics, diameter, blood flow velocity, and volumic flow of the brachial artery were studied before and after diltiazem administration in 11 patients with sustained essential hypertension. The study was compared with the hemodynamic effects of dihydralazine. The caliber of the brachial artery was evaluate...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:

    authors: Safar ME,Simon AC,Levenson JA,Cazor JL

    更新日期:1983-02-01 00:00:00

  • Angiogenesis and pericytes in the initiation of ectopic calcification.

    abstract::Ectopic calcification of blood vessels, heart valves, and skeletal muscle is a major clinical problem. There is now good evidence that angiogenesis is associated with ectopic calcification in these tissues and that it is necessary, but not sufficient, for calcification to occur. Angiogenesis may regulate ectopic calci...

    journal_title:Circulation research

    pub_type: 杂志文章,评审

    doi:10.1161/01.RES.0000163634.51301.0d

    authors: Collett GD,Canfield AE

    更新日期:2005-05-13 00:00:00

  • Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis.

    abstract::The mitochondrial enzyme monoamine oxidase (MAO), its isoform MAO-A, plays a major role in reactive oxygen species-dependent cardiomyocyte apoptosis and postischemic cardiac damage. In the current study, we investigated whether sphingolipid metabolism can account for mediating MAO-A- and reactive oxygen species-depend...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.RES.0000253900.66640.34

    authors: Pchejetski D,Kunduzova O,Dayon A,Calise D,Seguelas MH,Leducq N,Seif I,Parini A,Cuvillier O

    更新日期:2007-01-05 00:00:00

  • Bone morphogenetic protein signaling modulates myocardin transactivation of cardiac genes.

    abstract::Bone morphogenetic proteins (BMPs) play important roles in cardiovascular development. However, how BMP-signaling pathways regulate cardiac gene expression is less clear. We have previously identified myocardin as a cardiac and smooth muscle-specific transcriptional cofactor for serum response factor (SRF). Myocardin ...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.RES.0000190670.92879.7d

    authors: Callis TE,Cao D,Wang DZ

    更新日期:2005-11-11 00:00:00

  • Changes in myofibrillar activation and troponin C Ca2+ binding associated with troponin T isoform switching in developing rabbit heart.

    abstract::Postnatal development of the mammalian heart is associated with changes in the population of isoforms of the thin filament proteins. We correlated the change in thin filament proteins, which occur in rabbit hearts between 5 days and 22 days of age, with changes in Ca2+ dependence of myofibrillar ATPase activity, force...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.66.5.1204

    authors: McAuliffe JJ,Gao LZ,Solaro RJ

    更新日期:1990-05-01 00:00:00

  • Connexin 43 downregulation and dephosphorylation in nonischemic heart failure is associated with enhanced colocalized protein phosphatase type 2A.

    abstract::In nonischemic heart failure (HF), ventricular tachycardia initiates by a nonreentrant mechanism, but there is altered conduction (that could lead to re-entry) that could arise from changes in gap junctional proteins, especially connexin43 (Cx43). We studied Cx43 expression and phosphorylation state in the left ventri...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.RES.0000152325.07495.5a

    authors: Ai X,Pogwizd SM

    更新日期:2005-01-07 00:00:00

  • Heparin disrupts the CXCR4/SDF-1 axis and impairs the functional capacity of bone marrow-derived mononuclear cells used for cardiovascular repair.

    abstract:RATIONALE:Cell therapy is a promising option for the treatment of acute or chronic myocardial ischemia. The intracoronary infusion of cells imposes the potential risk of cell clotting, which may be prevented by the addition of anticoagulants. However, a comprehensive analysis of the effects of anticoagulants on the fun...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/CIRCRESAHA.112.265678

    authors: Seeger FH,Rasper T,Fischer A,Muhly-Reinholz M,Hergenreider E,Leistner DM,Sommer K,Manavski Y,Henschler R,Chavakis E,Assmus B,Zeiher AM,Dimmeler S

    更新日期:2012-09-14 00:00:00

  • Effects of cytosolic ATP on Ca(2+) sparks and SR Ca(2+) content in permeabilized cardiac myocytes.

    abstract::Confocal imaging was used to study the influence of cytosolic ATP on the properties of spontaneous Ca(2+) sparks in permeabilized ventricular myocytes. Cells were perfused with mock intracellular solutions containing fluo 3. Reducing [ATP] to <0.5 mmol/L decreased the frequency but increased the amplitude of spontaneo...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/hh1801.096264

    authors: Yang Z,Steele DS

    更新日期:2001-09-14 00:00:00

  • Nitric oxide/cAMP interactions in the control of rat renal vascular resistance.

    abstract::This study aimed to characterize the interaction between nitric oxide (NO)- and cAMP-related pathways in the control of renal blood flow. Using the isolated perfused rat kidney model, we determined the effects of inhibition of NO formation by Nomega-nitro-L-arginine methyl ester (L-NAME; 1 mmol/L) and of NO administra...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.84.2.186

    authors: Sandner P,Kornfeld M,Ruan X,Arendshorst WJ,Kurtz A

    更新日期:1999-02-05 00:00:00

  • Inflammation in myocardial diseases.

    abstract::Inflammatory processes underlie a broad spectrum of conditions that injure the heart muscle and cause both structural and functional deficits. In this article, we address current knowledge regarding 4 common forms of myocardial inflammation: myocardial ischemia and reperfusion, sepsis, viral myocarditis, and immune re...

    journal_title:Circulation research

    pub_type: 杂志文章,评审

    doi:10.1161/CIRCRESAHA.111.243170

    authors: Marchant DJ,Boyd JH,Lin DC,Granville DJ,Garmaroudi FS,McManus BM

    更新日期:2012-01-06 00:00:00

  • Phosphoinositide 3-kinase mediates enhanced spontaneous and agonist-induced contraction in aorta of deoxycorticosterone acetate-salt hypertensive rats.

    abstract::Arteries from deoxycorticosterone acetate (DOCA)-salt and N(omega)-nitro-L-arginine (L-NNA) hypertensive but not normotensive rats develop spontaneous tone. LY294002 and wortmannin, phosphoinositide 3-kinase (PI3-kinase) inhibitors, eliminate spontaneous tone. We hypothesized that PI3-kinase protein and/or activity wa...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.0000030861.13850.f1

    authors: Northcott CA,Poy MN,Najjar SM,Watts SW

    更新日期:2002-08-23 00:00:00

  • Progressive increases in complexity of T-wave oscillations herald ischemia-induced ventricular fibrillation.

    abstract::T-wave alternans (TWA), an ABAB oscillation, has been postulated as the initial pattern in a stepwise progression to higher-order oscillations, culminating in sudden arrhythmic death. The present study is the first to provide experimental evidence to support this intriguing concept. Epicardial and endocardial ECGs fro...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.0000038887.17976.33

    authors: Nearing BD,Verrier RL

    更新日期:2002-10-18 00:00:00

  • Dilatation of cerebral arterioles in response to activation of adenylate cyclase is dependent on activation of Ca(2+)-dependent K+ channels.

    abstract::The role of Ca(2+)-dependent potassium channels in mediating vascular responses to activation of adenylate cyclase in vivo is not known. The goal of this study was to examine the hypothesis that dilatation of cerebral arterioles in response to activation of adenylate cyclase is mediated by activation of Ca(2+)-depende...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.76.6.1057

    authors: Taguchi H,Heistad DD,Kitazono T,Faraci FM

    更新日期:1995-06-01 00:00:00

  • Protein kinase C activation contributes to microvascular barrier dysfunction in the heart at early stages of diabetes.

    abstract::The functional disturbance of microvasculature is recognized as an initiating mechanism that underlies the development of various diabetic complications. Although a causal relationship between microvascular leakage and tissue damage has been well documented in diabetic kidneys and eyes, there is a lack of information ...

    journal_title:Circulation research

    pub_type: 杂志文章

    doi:10.1161/01.res.87.5.412

    authors: Yuan SY,Ustinova EE,Wu MH,Tinsley JH,Xu W,Korompai FL,Taulman AC

    更新日期:2000-09-01 00:00:00