Protein-, gene-, and cell-based therapeutic angiogenesis for the treatment of myocardial ischemia

Ruel, Marc; Song, Junhui; Sellke, Frank W.

doi:10.1023/b:mcbi.0000044381.01098.03

Cited by 20 publications

(12 citation statements)

References 111 publications

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“…Previous studies have clearly demonstrated a critical role for vascular NO bioavailability in regulating angiogenic responses (31,39,44). Furthermore, our recent studies have strongly suggested that a chronic reduction in vascular NO bioavailability may represent a major contributing mechanism underlying the progressive skeletal muscle microvascular rarefaction in the metabolic syndrome (13).…”

Section: Discussionmentioning

confidence: 88%

“…A growing number of previous studies have indicated that the imposition of a chronic exercise regimen will increase endothelial NOS (eNOS) expression and activity, with the cumulative result of increasing NO bioavailability under con-trol conditions (4,19,29,52) and in animal models of type I diabetes mellitus (37), heart failure (55), aging (44,49), and the metabolic syndrome (1). Taken together with our previous work and that from Matsunaga et al (35,36), the present study was designed to test the hypothesis that imposition of a chronic exercise regimen would increase vascular NO bioavailability in OZR and blunt peripheral microvascular rarefaction.…”

mentioning

confidence: 99%

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Exercise training blunts microvascular rarefaction in the metabolic syndrome

Frisbee¹,

Samora²,

Peterson³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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son, and Randall Bryner. Exercise training blunts microvascular rarefaction in the metabolic syndrome. Am J Physiol Heart Circ Physiol 291: H2483-H2492, 2006. First published June 23, 2006 doi:10.1152/ajpheart.00566.2006.-Reduced skeletal muscle microvessel density (MVD) in the obese Zucker rat (OZR) model of the metabolic syndrome is a function of a chronic reduction in vascular nitric oxide (NO) bioavailability. Previous studies suggest that exercise can improve NO bioavailability and reduce chronic inflammation and that low vascular NO bioavailability may be associated with impaired angiogenic responses via increased matrix metalloproteinase (MMP)-2 and MMP-9 activity. As such, we hypothesized that chronic exercise (EX) would increase NO bioavailability in OZR and blunt microvascular rarefaction through reduced MMP activity, and potentially via altered plasma cytokine levels. Ten weeks of treadmill exercise (1 h/day, 5 days/wk, 22 m/min) reduced body mass and fasting insulin and triglyceride levels in EX-OZR vs. sedentary (SED) OZR. In EX-OZR, gastrocnemius muscle MVD was improved by 19 Ϯ 4%, whereas skeletal muscle arteriolar dilation and conduit arterial methacholine-induced NO release were increased. In EX-OZR, functional hyperemia was improved vs. SED-OZR, and minimum vascular resistance within perfused gastrocnemius muscle was reduced, although no change in arteriolar stiffness was identified. Western blotting and gelatin zymography demonstrated that neither expression nor activity of MMP-2 or MMP-9 was altered in skeletal muscle of EX vs. SED animals. Plasma markers of inflammation associated with angiogenesis, monocyte chemoattractant protein-1 and IL-1␤, were increased in SED-OZR and were reduced with training, whereas IL-13 was reduced in SED-OZR and increased with exercise. These data suggest that exercise-induced improvements in skeletal muscle MVD in OZR are associated with increased NO bioavailability and may stem from altered inflammatory profiles rather than MMP function. skeletal muscle microcirculation; regulation of skeletal muscle perfusion; microvessel density; vascular remodeling; vascular resistance THE OBESE ZUCKER RAT (OZR) is a model of the metabolic syndrome based on chronic hyperphagia (5, 21). As such, this animal model rapidly becomes obese and develops profound insulin resistance and hypertriglyceridemia, with a clinically relevant hypertension and the genesis of a prothrombotic and proinflammatory state (2,17,24,51). We have previously demonstrated that, with evolution of the metabolic syndrome in the OZR, a progressive reduction in skeletal muscle microvessel density develops that can result in 25% reduction in the total number of microvessels within this tissue compared with levels determined in control animals (14). This rarefaction of the vascular network contributes to an elevation in peripheral vascular resistance in OZR (12, 14, 15) and appears to be largely independent of any developing increase in mean arterial pressure (13). In contrast, ongoing studies in our laborat...

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Section: Discussionmentioning

confidence: 88%

mentioning

confidence: 99%

Exercise training blunts microvascular rarefaction in the metabolic syndrome

Frisbee¹,

Samora²,

Peterson³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…The regeneration or formation of blood vessels in the adult heart may occur simultaneously by both vasculogenesis and angiogenesis [1]. Endothelial progenitor cells participate in both processes and are important for vascular repair and maintenance [2].…”

Section: Introductionmentioning

confidence: 99%

Generation of CD133+ cells from CD133− peripheral blood mononuclear cells and their properties

Suuronen

Wong

Kapila

et al. 2006

Cardiovascular Research

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These results demonstrate a source of blood CD133+ cells other than direct mobilization from the bone marrow. Cellular interaction was observed between fractions, with CD133+ cells showing better in vitro function in the presence of CD133- cells. These findings provide a novel source for CD133+ cells and a rationale for the investigation of angiogenic cell recruitment or delivery strategies involving more than one cell type at ischemic sites.

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“…Our current study uniquely studied proliferation and migration of adult mature aortic endothelial cells, and endothelial outgrowth from adult mouse aortic discs to examine the angiogenic effects of netrin-1. Compared to umbilical vein or developing vessels, aorta shares the closest physiology with large adult coronary arteries where therapeutic angiogenesis is beneficial for patients with ischemic coronary artery diseases (9,10). More importantly, the signaling mechanisms underlying netrin-1 modulation of angiogenesis were identified.…”

mentioning

confidence: 99%

Netrin-1 induces angiogenesis via a DCC-dependent ERK1/2-eNOS feed-forward mechanism

Nguyen

Cai

2006

Proc. Natl. Acad. Sci. U.S.A.

150

152

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Netrin-1 is critical for axonal pathfinding which shares similarities with formation of vascular network. Here we report that netrin-1 induction of angiogenesis is mediated by an increase in endothelial nitric oxide (NO ⅐ ) production, which occurs via a DCC-dependent, ERK1͞2-eNOS feed-forward mechanism. Exposure of mature aortic endothelial cells to netrin-1 resulted in a potent, dose-dependent increase in NO ⅐ production, detected by electron spin resonance. Scavenging NO ⅐ with 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (PTIO) abolished netrin-1 stimulated angiogenesis. Netrin-1-stimulated NO ⅐ production or angiogenesis was inhibited by DCC antibody, DCC small interfering RNA (siRNA), specific inhibitors (PD98059, U0126), or siRNAs for MEK1͞2. PTIO attenuated ERK1͞2 phosphorylation, indicating a feed-forward mechanism. Netrin-1 induced a time-dependent phosphorylation of eNOS s1179, s116 and a rapid dephosphorylation of eNOSt497. Only eNOS s1179 was sensitive to U0126 or PTIO. These data characterized a mechanism whereby netrin-1 promotes angiogenesis, which may broadly relate to cardiovascular, neuronal and cancer physiology.nitric oxide N etrin-1 is one of the first discovered axon-guiding molecules that are critical for neuronal development (1, 2). It is a secreted protein that is released to circulation after being produced by a variety of cells (3). Upon activation of its attraction-selective receptor deleted in colorectal cancer (DCC) or neogenin, netrin-1 induces axonal outgrowth and crossover through the midline (2, 4); this is at least partially mediated by activation of the mitogen activated protein kinase ERK1͞2 (5).Formation of vascular network shares many similarities with neuronal pathfinding (6). A number of mitogens including VEGF and EGF have been shown to regulate endothelial cell growth and proliferation. Interestingly, netrin-1 is structurally homologous to the endothelial mitogens. It has an N-terminal type IV laminin repeat, followed by three cystein-rich EGF modules and a positively charged C-terminal domain. A recent study demonstrated that netrin-1 stimulates growth of umbilical vein endothelial cells and vascular smooth muscle (7). However, in the presence of the repulsive receptor UNC5B in developing capillaries, netrin-1 induces endothelial filopodial retraction (8). Our current study uniquely studied proliferation and migration of adult mature aortic endothelial cells, and endothelial outgrowth from adult mouse aortic discs to examine the angiogenic effects of netrin-1. Compared to umbilical vein or developing vessels, aorta shares the closest physiology with large adult coronary arteries where therapeutic angiogenesis is beneficial for patients with ischemic coronary artery diseases (9, 10). More importantly, the signaling mechanisms underlying netrin-1 modulation of angiogenesis were identified.Using the highly specific and sensitive electron spin resonance technology for direct and characteristic measurement of nitric oxide gas radical (NO ⅐ ), we examined a potent...

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Protein-, gene-, and cell-based therapeutic angiogenesis for the treatment of myocardial ischemia

Cited by 20 publications

References 111 publications

Exercise training blunts microvascular rarefaction in the metabolic syndrome

Exercise training blunts microvascular rarefaction in the metabolic syndrome

Generation of CD133+ cells from CD133− peripheral blood mononuclear cells and their properties

Netrin-1 induces angiogenesis via a DCC-dependent ERK1/2-eNOS feed-forward mechanism

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