Abstract:
RATIONALE:We previously reported that vascular endothelial growth factor (VEGF)-induced binding of VEGF receptor 2 (VEGFR2) to epsins 1 and 2 triggers VEGFR2 degradation and attenuates VEGF signaling. The epsin ubiquitin interacting motif (UIM) was shown to be required for the interaction with VEGFR2. However, the molecular determinants that govern how epsin specifically interacts with and regulates VEGFR2 were unknown. OBJECTIVE:The goals for the present study were as follows: (1) to identify critical molecular determinants that drive the specificity of the epsin and VEGFR2 interaction and (2) to ascertain whether such determinants were critical for physiological angiogenesis in vivo. METHODS AND RESULTS:Structural modeling uncovered 2 novel binding surfaces within VEGFR2 that mediate specific interactions with epsin UIM. Three glutamic acid residues in epsin UIM were found to interact with residues in VEGFR2. Furthermore, we found that the VEGF-induced VEGFR2-epsin interaction promoted casitas B-lineage lymphoma-mediated ubiquitination of epsin, and uncovered a previously unappreciated ubiquitin-binding surface within VEGFR2. Mutational analysis revealed that the VEGFR2-epsin interaction is supported by VEGFR2 interacting specifically with the UIM and with ubiquitinated epsin. An epsin UIM peptide, but not a mutant UIM peptide, potentiated endothelial cell proliferation, migration and angiogenic properties in vitro, increased postnatal retinal angiogenesis, and enhanced VEGF-induced physiological angiogenesis and wound healing. CONCLUSIONS:Distinct residues in the epsin UIM and VEGFR2 mediate specific interactions between epsin and VEGFR2, in addition to UIM recognition of ubiquitin moieties on VEGFR2. These novel interactions are critical for pathophysiological angiogenesis, suggesting that these sites could be selectively targeted by therapeutics to modulate angiogenesis.
journal_name
Circ Resjournal_title
Circulation researchauthors
Rahman HNA,Wu H,Dong Y,Pasula S,Wen A,Sun Y,Brophy ML,Tessneer KL,Cai X,McManus J,Chang B,Kwak S,Rahman NS,Xu W,Fernandes C,Mcdaniel JM,Xia L,Smith L,Srinivasan RS,Chen Hdoi
10.1161/CIRCRESAHA.115.307679subject
Has Abstractpub_date
2016-03-18 00:00:00pages
957-969issue
6eissn
0009-7330issn
1524-4571journal_volume
118pub_type
杂志文章abstract::L-type Ca(2+) channel (LTCC) blockers, represented by amlodipine and verapamil, are widely used antihypertensive drugs that also have antiinflammatory activities. Plasminogen (Plg) is an important mediator of macrophage recruitment, and this role depends on its interaction with Plg receptors (Plg-Rs). Plg-Rs include h...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.109.200311
更新日期:2009-07-17 00:00:00
abstract::During myocardial ischemia, electrical uncoupling and contracture herald irreversible damage. In the present study, we tested the hypothesis that an increase of intracellular Ca2+ is an important factor initiating these events. Therefore, we simultaneously determined tissue resistance, mechanical activity, pH(0), and ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.79.2.237
更新日期:1996-08-01 00:00:00
abstract:RATIONALE:Human heregulins, neuregulin-1 type I polypeptides that activate proliferation, differentiation, and survival of glial cells, neurons, and myocytes, are expressed in macrophage foam cells within human coronary atherosclerotic lesions. Macrophage foam cell formation, characterized by cholesterol ester accumula...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.109.193870
更新日期:2009-08-28 00:00:00
abstract::To test the hypothesis that the capacity to develop left ventricular (LV) hypertrophy might diminish with advancing age, we examined the hypertrophic response to ascending aortic constriction in 3 groups of adult Fischer 344 rats (9 months, 18 months, and 22 months of age). Aortic constriction was created so that aort...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.61.3.337
更新日期:1987-09-01 00:00:00
abstract:RATIONALE:Sustained cardiac hypertrophy is often accompanied by maladaptive cardiac remodeling leading to decreased compliance and increased risk for heart failure. Maladaptive hypertrophy is considered to be a therapeutic target for heart failure. MicroRNAs (miRNAs) and long noncoding RNAs (lncRNAs) have various biolo...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.114.302476
更新日期:2014-04-25 00:00:00
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
更新日期:2016-01-22 00:00:00
abstract::The myocardium of the failing heart undergoes a number of structural alterations, most notably hypertrophy of cardiac myocytes and an increase in extracellular matrix proteins, often seen as primary fibrosis. Connective tissue growth factor (CTGF) is a key molecule in the process of fibrosis and therefore seems an att...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.108.182535
更新日期:2009-01-30 00:00:00
abstract::Therapy directed against the toxic effects of reactive oxygen species may reduce the final extent of ischemic injury in otherwise viable tissue irreversibly injured by the abrupt reoxygenation of reperfusion. In four groups of dogs, superoxide dismutase plus catalase (groups I-III) or saline (controls) (group IV) was ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.54.3.277
更新日期:1984-03-01 00:00:00
abstract::Several time- and voltage-dependent ionic currents have been identified in cardiac pacemaker cells, including Na(+) current, L- and T-type Ca(2+) currents, hyperpolarization-activated cation current, and various types of delayed rectifier K(+) currents. Mathematical models have demonstrated that spontaneous action pot...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.res.87.2.88
更新日期:2000-07-21 00:00:00
abstract::Morphometric data from stable (nonedematous) isolated dog lungs, perfused with nearly cell-free perfusates, were compared to similar stereological evaluations of isolated dog lungs after induction of severe acute hydrostatic edema. In the edematous lungs, capillary surface and volume densities were substantially incre...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.43.1.72
更新日期:1978-07-01 00:00:00
abstract::Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected molecules that function in the developmental pathways involved in myocyte specification, differentiation, or cardiac morphogene...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.112.300853
更新日期:2013-02-15 00:00:00
abstract::Abstract: Macrophages, a key component of the innate defense against pathogens, participate in the initiation and resolution of inflammation, and in the maintenance of tissues. These diverse and at times antithetical functions of macrophages are executed via distinct activation states, ranging from classical to altern...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.110.216523
更新日期:2010-05-28 00:00:00
abstract::To investigate the spread of contraction in the rabbit ear artery, changes in segment diameter were measured after local stimulation. No spread of contraction was produced by direct current or local application of norepinephrine (NE). Repetitive electrical stimulation caused contraction which spread far from the point...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.49.3.600
更新日期:1981-09-01 00:00:00
abstract::Previously, we have reported on the selective accumulation of an atrial-like myosin light chain-1 (ALC1) in different forms of human ventricular hypertrophy. The present study involves the determination of ALC1 content in a control group and in patients with aortic stenosis or insufficiency before and 56 +/- 23 months...
journal_title:Circulation research
pub_type: 临床试验,杂志文章
doi:10.1161/01.res.70.5.1035
更新日期:1992-05-01 00:00:00
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
更新日期:1983-12-01 00:00:00
abstract::Ryanodine receptor (RyR) phosphorylation by protein kinase A (PKA) may be important in modulating resting sarcoplasmic reticulum (SR) Ca2+ release, especially in heart failure. However, clear cellular data on PKA-dependent modulation of cardiac RyRs is limited because of difficulty in distinguishing between PKA effect...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/hh0302.105660
更新日期:2002-02-22 00:00:00
abstract::Adenosine modulates a variety of cellular functions by interacting with specific cell surface G protein-coupled receptors (A1, A2A, A2B, and A3) and is a potential mediator of angiogenesis through the A2B receptor. The lack of a potent, selective A2B receptor inhibitor has hampered its characterization. Our goal was t...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000091260.78959.BC
更新日期:2003-09-19 00:00:00
abstract::By use of gene targeting and/or transgenesis, it is now possible to make defined changes in genes whose functions underlie mammalian cardiovascular function. Because of technical and economic considerations, these experiments are largely confined to the mouse. Genetic modification of the loci responsible for aspects o...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.res.82.4.407
更新日期:1998-03-09 00:00:00
abstract::We have previously shown that a cryoactivatable inactive form of renin, which we have tentatively termed prorenin, occurs in human plasma. Plasma prorenin is measured by subtracting the endogenous plasma renin activity (PRA) from the total renin activity measured after cryoactivation. Cryoactivation is accomplished by...
journal_title:Circulation research
pub_type: 杂志文章
doi:
更新日期:1977-05-01 00:00:00
abstract::The purpose of these studies was to evaluate cardiovascular structural and functional changes in a model of hypertension-induced myocardial hypertrophy in which vasodilator therapy decreased blood pressure to normal levels. Thus, we determined the separate contributions of hypertension and hypertrophy on myocardial an...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.64.6.1127
更新日期:1989-06-01 00:00:00
abstract::Despite intense interest in understanding the differentiation of vascular smooth muscle, very little is known about the cellular and molecular mechanisms that control differentiation of this cell type. Progress in this field has been hampered by the lack of an inducible in vitro system for study of the early steps of ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.76.5.742
更新日期:1995-05-01 00:00:00
abstract::The plateau phase of prolonged Sr-mediated contractions of preparations of cat and frog heart muscle was used to study the transient response to abrupt changes in load or length. An oscillatory response (total amplitude equal to or less than 5% Lmax) was obtained. Isotonic oscillations were less damped than their isom...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.38.4.289
更新日期:1976-04-01 00:00:00
abstract::It has been shown previously that serotonin stimulates the production of prostacyclin by bovine aortic smooth muscle cells in culture, via 5-HT2 receptors (Coughlin SR, Moskowitz MA, Antoniades HN, Levine L. Proc Natl Acad Sci USA 1981;78:7134-7138). These cells express a synthetic phenotype, whereas the majority of t...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.64.4.806
更新日期:1989-04-01 00:00:00
abstract::The extracellular epicardial potential fields produced by simple depolarization waves in the in situ canine left ventricular myocardium were analyzed. A mathematical model that included tissue anisotrophy was developed to explain the observed fields. Values of intracellular (i), extracellular (o), longitudinal (l), an...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.50.3.342
更新日期:1982-03-01 00:00:00
abstract:RATIONALE:Microparticles are cell-derived membrane vesicles, relevant to a range of biological responses and known to be elevated in cardiovascular disease. OBJECTIVE:To investigate microparticle release during cardiac stress and how this response differs in those with vascular disease. METHODS AND RESULTS:We measure...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.114.301904
更新日期:2014-01-03 00:00:00
abstract::Ventricular arrhythmias that accompany myocardial infarction in dogs may be secondary to the altered electrophysiological properties of the subendocardial Purkinje fibers that survive 24 hours after the coronary occlusion. To better understand the ionic mechanisms that underlie the altered electrical activity of these...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.65.4.955
更新日期:1989-10-01 00:00:00
abstract::F2-Isoprostanes are novel bioactive prostaglandin F2-like compounds produced by nonenzymatic free radical-catalyzed peroxidation of arachidonic acid. F2-Isoprostanes are initially formed in situ on phospholipids and subsequently released. Quantification of the F2-isoprostanes has been found to represent a valuable and...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.77.2.335
更新日期:1995-08-01 00:00:00
abstract::Platelet hyperactivity associated with hyperlipidemia may contribute to development of a prothrombotic state. We previously showed that oxidized low-density lipoprotein (oxLDL) formed in the setting of hyperlipidemia and atherosclerosis activated platelets in a CD36-dependent manner. We now show that mitogen-activated...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.108.172064
更新日期:2008-06-20 00:00:00
abstract:RATIONALE:Higher social integration is associated with lower cardiovascular mortality; however, whether it is associated with incident coronary heart disease (CHD), especially in women, and whether associations differ by case fatality are unclear. OBJECTIVES:This study sought to examine the associations between social...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.116.309443
更新日期:2017-06-09 00:00:00
abstract::A series of new phenylethanolamines with 2-methoxy and/or 4-methyl, 4-chloro, or 4-bromo ring substituents and either N-isopropyl or N-tert butyl substituents have been synthesized and tested for beta 1- and beta 2-adrenoceptor blocking activity using isolated guinea pig atrial and tracheal preparations. Each of the d...
journal_title:Circulation research
pub_type: 杂志文章
doi:
更新日期:1980-06-01 00:00:00