Abstract:
:Although vascular endothelial growth factor (VEGF) has been described as a potent angiogenic stimulus, its application in therapy remains difficult: blood vessels formed by exposure to VEGF tend to be malformed and leaky. In nature, the principal form of VEGF possesses a binding site for ECM components that maintain it in the immobilized state until released by local cellular enzymatic activity. In this study, we present an engineered variant form of VEGF, alpha2PI1-8-VEGF121, that mimics this concept of matrix-binding and cell-mediated release by local cell-associated enzymatic activity, working in the surgically-relevant biological matrix fibrin. We show that matrix-conjugated alpha2PI1-8-VEGF121 is protected from clearance, contrary to native VEGF121 mixed into fibrin, which was completely released as a passive diffusive burst. Grafting studies on the embryonic chicken chorioallantoic membrane (CAM) and in adult mice were performed to assess and compare the quantity and quality of neovasculature induced in response to fibrin implants formulated with matrix-bound alpha2PI1-8-VEGF121 or native diffusible VEGF121. Our CAM measurements demonstrated that cell-demanded release of alpha2PI1-8-VEGF121 increases the formation of new arterial and venous branches, whereas exposure to passively released wild-type VEGF121 primarily induced chaotic changes within the capillary plexus. Specifically, our analyses at several levels, from endothelial cell morphology and endothelial interactions with periendothelial cells, to vessel branching and network organization, revealed that alpha2PI1-8-VEGF121 induces vessel formation more potently than native VEGF121 and that those vessels possess more normal morphologies at the light microscopic and ultrastructural level. Permeability studies in mice validated that vessels induced by alpha2PI1-8-VEGF121 do not leak. In conclusion, cell-demanded release of engineered VEGF121 from fibrin implants may present a therapeutically safe and practical modality to induce local angiogenesis.
journal_name
Circ Resjournal_title
Circulation researchauthors
Ehrbar M,Djonov VG,Schnell C,Tschanz SA,Martiny-Baron G,Schenk U,Wood J,Burri PH,Hubbell JA,Zisch AHdoi
10.1161/01.RES.0000126411.29641.08subject
Has Abstractpub_date
2004-04-30 00:00:00pages
1124-32issue
8eissn
0009-7330issn
1524-4571pii
01.RES.0000126411.29641.08journal_volume
94pub_type
杂志文章abstract::Catecholamines and catecholamine-synthesizing enzymes have been examined in specific brain areas during the development of spontaneously (genetic) hypertensive (SH) rats. Changes in catecholamine metabolism were localized to regions of the brain implicated in the regulation of blood pressure. Norepinephrine levels and...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.42.4.529
更新日期:1978-04-01 00:00:00
abstract::Vascular disease often involves vessel hypertrophy with underlying cellular hypertrophy or hyperplasia. Experimental diabetes stimulates hypertrophy of the rat mesenteric vasculature, and we investigated the hypothesis that this hypertrophy is associated with activation of Na(+)-H(+) exchange (NHE) activity. We measur...
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pub_type: 杂志文章,随机对照试验
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abstract::Angiotensin II and its metabolites, [des-Asp-1]-angiotensin II (angiotensin III), [des-(Asp-1,Arg-2)]angiotensin II, and [des-(Asp-1,Arg-2,val-3)]angiotensin II, were measured in arterial and venous plasma from normal rats. Paper chromatography was used to separate the peptides which were measured with a radioimmunoas...
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doi:10.1161/01.res.38.6.122
更新日期:1976-06-01 00:00:00
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doi:10.1161/CIRCRESAHA.111.258871
更新日期:2012-02-03 00:00:00
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doi:10.1161/01.res.40.4.348
更新日期:1977-04-01 00:00:00
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doi:10.1161/CIRCRESAHA.116.310367
更新日期:2017-03-03 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.86.1.94
更新日期:2000-01-07 00:00:00
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doi:10.1161/01.res.86.2.152
更新日期:2000-02-04 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.52.3.280
更新日期:1983-03-01 00:00:00
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
更新日期:1999-09-17 00:00:00
abstract::Activity was recorded from physiologically identified baroreceptor or chemoreceptor fibers in carotid sinus nerves of urethane-anesthetized spontaneously breathing rabbits. A carotid sinus area was vascularly isolated so that carotid sinus pressure and perfusion medium (Locke's solution or rabbit blood) could be contr...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.69.6.1608
更新日期:1991-12-01 00:00:00
abstract::Heparin has growth inhibitory effects on pulmonary artery smooth muscle cell (PASMC) in vitro and in vivo. However, the mechanism has not been fully defined. In this study, we investigated the role of cyclin-dependent kinase inhibitors, p21(WAF1/cip1) (p21) and p27Kip1 (p27), in the inhibitory effect of heparin on PAS...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000188211.83193.1a
更新日期:2005-10-28 00:00:00
abstract::Whole-cell voltage-clamp experiments were performed on enzymatically dissociated single ventricular myocytes harvested from feline endocardial and epicardial surfaces. The studies were designed to test the hypothesis that the differences in the amplitude of transient outward current (Ito) contribute to the difference ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.67.5.1287
更新日期:1990-11-01 00:00:00
abstract::Diabetes mellitus has profound adverse effects on vascular and, in particular, endothelial function. Although pressure-induced constriction ("myogenic tone") is a major contributor to the regulation of blood flow, little is known about the effects of diabetes on this response. Diabetes has been shown to diminish the d...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.81.6.996
更新日期:1997-12-01 00:00:00
abstract::Endothelins exert potent excitatory cardiac effects by acting on specific receptors on myocytes. In this study, we have examined the signal transduction mechanism for the chronotropic effect of endothelins in guinea pig atria. A competition binding of [125I]endothelin 1 ([125I]ET-1) using the recently developed ETA re...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.76.2.284
更新日期:1995-02-01 00:00:00
abstract::Receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules and engages diverse ligands relevant to distinct pathological processes. One class of RAGE ligands includes glycoxidation products, termed advanced glycation end products, which occur in diabetes...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.res.84.5.489
更新日期:1999-03-19 00:00:00
abstract:RATIONALE:The ubiquitin-proteasome system (UPS) and the autophagic-lysosomal pathway are pivotal to proteostasis. Targeting these pathways is emerging as an attractive strategy for treating cancer. However, a significant proportion of patients who receive a proteasome inhibitor-containing regime show cardiotoxicity. Mo...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.119.316007
更新日期:2020-07-31 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/01.res.0000046452.67724.b8
更新日期:2002-12-13 00:00:00
abstract:RATIONALE:Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear. OBJECTIVE:To determine how mitochond...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.113.301319
更新日期:2013-09-13 00:00:00
abstract::Oxidized low-density lipoproteins increase arginase activity and reciprocally decrease endothelial NO in human aortic endothelial cells. Here, we demonstrate that vascular endothelial arginase activity is increased in atherogenic-prone apolipoprotein E-null (ApoE(-/-)) and wild-type mice fed a high cholesterol diet. I...
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pub_type: 杂志文章
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更新日期:2008-04-25 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.66.1.218
更新日期:1990-01-01 00:00:00
abstract::To determine whether the attenuation in the growth capacity of myocytes in the overloaded aging heart is associated with an impairment in the activation of insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) in the stressed cells, large myocardial infarcts were produced in Fischer 344 rats at 4 and 16 month...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.78.4.536
更新日期:1996-04-01 00:00:00
abstract::Whole-cell voltage-clamp experiments and single-channel current recordings in cell-attached patch mode were performed on enzymatically dissociated single ventricular myocytes harvested from feline endocardial and epicardial surfaces. The studies were designed to compare the characteristics of inward rectifier K+ curre...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.70.1.91
更新日期:1992-01-01 00:00:00
abstract::Although clinical trials of cell-based approaches to cardiovascular disease have yielded some promising results, no cell-based therapy has achieved regulatory approval for a cardiovascular indication. To broadly assess the challenges to regulatory approval and identify strategies to facilitate this goal, the Cardiac S...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.118.313261
更新日期:2018-08-03 00:00:00
abstract::The expression of angiotensin II type 2 (AT(2)) receptor is closely associated with cell growth, differentiation, and/or injury. We examined the effect of interferon (IFN)-gamma on AT(2) receptor expression in mouse fibroblast R3T3 cells and demonstrated that IFN-gamma treatment increased the expression of AT(2) recep...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.86.2.233
更新日期:2000-02-04 00:00:00
abstract:RATIONALE:Pulmonary hypertensive remodeling is characterized by excessive proliferation, migration, and proinflammatory activation of adventitial fibroblasts. In culture, fibroblasts maintain a similar activated phenotype. The mechanisms responsible for generation/maintenance of this phenotype remain unknown. OBJECTIV...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.114.301633
更新日期:2014-01-03 00:00:00
abstract::Animal and preliminary human studies of adult cell therapy following acute myocardial infarction have shown an overall improvement of cardiac function. Myocardial and vascular regeneration have been initially proposed as mechanisms of stem cell action. However, in many cases, the frequency of stem cell engraftment and...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.108.176826
更新日期:2008-11-21 00:00:00
abstract::The relations between atrial natriuretic peptide (ANP) binding sites in the renal medulla, plasma ANP concentration, and ventricular dysfunction have been studied in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. Plasma ANP concentration was measured by radioimmunoassay, and quantit...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.62.1.155
更新日期:1988-01-01 00:00:00
abstract::We evaluated the hypothesis that stunning swine myocardium with brief ischemia reduces oxygen demand in the stunned region and increases tolerance of myocardium to longer periods of ischemia. Wall function was quantified with ultrasonic crystals aligned to measure wall thickening, and stunning was achieved with two cy...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.66.4.1133
更新日期:1990-04-01 00:00:00