Fibroblast growth factor 2 affects vascular remodeling after acute myocardial infarction
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Ventricular remodeling
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Pathogenesis
Coronary arteries
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Abstract The effects of bone marrow cell transplantation (BMT) on myocardial infarct might be affected by host intrinsic circumferences. A best vascular niche was shown in the infarcted hearts with collateral vessels at 2 weeks after myocardial infarction (MI). BMT caused the greatest cardiac repairs after MI in the swine with better collateral vessels, which might be relative to richer collateral vessels, greater vessel densities, and higher expressions of basif fibroblast growth factor and stromal cell–derived factor-1 in the hearts before BMT. Our data suggest that existence of intrinsic collateral vessels contributes greatly to the beneficial effects of intracoronary BMT on cardiac repairs after MI. Disclosure of potential conflicts of interest is found at the end of this article.
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Cardiac Fibrosis
BETA (programming language)
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Placental growth factor (PlGF) has a distinct biological phenotype with a predominant proangiogenic role in disease without affecting quiescent vessels in healthy organs. We tested whether systemic administration of recombinant human (rh)PlGF improves regional myocardial blood flow (MBF) and systolic function recovery in a porcine chronic myocardial ischemia model. We implanted a flow-limiting stent in the proximal left anterior descending coronary artery and measured systemic hemodynamics, regional myocardial function using MRI, and blood flow using colored microspheres 4 wk later. Animals were then randomized in a blinded way to receive an infusion of rhPlGF (15 μg·kg(-1)·day(-1), n = 9) or PBS (control; n = 10) for 2 wk. At 8 wk, myocardial perfusion and function were reassessed. Infusion of rhPlGF transiently increased PlGF serum levels >30-fold (1,153 ± 180 vs. 33 ± 18 pg/ml at baseline, P < 0.001) without affecting systemic hemodynamics. From 4 to 8 wk, rhPlGF increased regional MBF from 0.46 ± 0.11 to 0.85 ± 0.16 ml·min(-1)·g(-1), with a concomitant increase in systolic wall thickening from 11 ± 3% to 26 ± 5% in the ischemic area. In control animals, no significant changes from 4 to 8 wk were observed (MBF: 0.45 ± 0.07 to 0.49 ± 0.08 ml·min(-1)·g(-1) and systolic wall thickening: 14 ± 4% to 18 ± 1%). rhPlGF-induced functional improvement was accompanied by increased myocardial neovascularization, enhanced glycogen utilization, and reduced oxidative stress and cardiomyocyte apoptosis in the ischemic zone. In conclusion, systemic rhPlGF infusion significantly enhances regional blood flow and contractile function of the chronic ischemic myocardium without adverse effects. PlGF protein infusion may represent an attractive therapeutic strategy to increase myocardial perfusion and energetics in chronic ischemic cardiomyopathy.
Coronary circulation
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Background Prevention of adverse remodeling after myocardial infarction ( MI) is an important goal of stem cell therapy. Clinical trial results vary, however, and poor cell retention and survival after delivery likely limit the opportunity to exert beneficial effects. To overcome these limitations, we built an implantable intravascular bioreactor ( IBR ) designed to protect contained cells from washout, dilution, and immune attack while allowing sustained release of beneficial paracrine factors. Methods and Results IBR s were constructed using semipermeable membrane adhered to a clinical‐grade catheter shaft. Mesenchymal stem cell ( MSC ) viability in and paracrine factor release from IBR s were assessed in vitro and IBR biocompatibility and immune protection confirmed in vivo. In a porcine anterior MI model, IBR s containing 25 million allogeneic MSC s ( IBR ‐ MSCs ) were compared with IBR s containing media alone ( IBR ‐Placebo; n=8 per group) with adverse remodeling assessed by magnetic resonance imaging. Four weeks after MI , IBR ‐ MSCs had no significant change in end‐diastolic volume (+0.33±4.32 mL; P =0.89), end‐systolic volume (+2.14±4.13 mL; P =0.21), and left ventricular ejection fraction (−2.27±2.94; P =0.33) while IBR ‐Placebo had significant increases in end‐diastolic volume (+10.37±3.84 mL; P =0.01) and ESV (+11.35±2.88 mL; P =0.01), and a significant decrease in left ventricular ejection fraction (−5.78±1.70; P =0.025). Eight weeks after MI , adherent pericarditis was present in 0 of 8 IBR ‐ MSCs versus 4 of 8 IBR ‐Placebo ( P =0.02), suggesting an anti‐inflammatory effect. In a separate study, 25 million allogeneic pig MSC s directly injected in the peri‐infarct zone 3 days after MI (n=6) showed no significant benefit in adverse remodeling at 4 weeks compared with IBR ‐ MSCs . Conclusions MSC s deployed inside an implantable, removable, and potentially rechargeable bioreactor in a large animal model remain viable, are immunoprotected, and attenuate adverse remodeling 4 weeks after MI .
Stem Cell Therapy
Ventricular remodeling
Cell therapy
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The acute phase of myocardial infarction (MI) is accompanied by edema contributing to tissue damage and disease outcome. Here, we aimed to identify the mechanism whereby vascular endothelial growth factor (VEGF)-A induces myocardial edema in the acute phase of MI to eventually promote development of therapeutics to specifically suppress VEGFA-regulated vascular permeability while preserving collateral vessel formation.VEGFA regulates vascular permeability and edema by activation of VEGF receptor-2 (VEGFR2), leading to induction of several signaling pathways including the cytoplasmic tyrosine kinase c-Src. The activated c-Src in turn phosphorylates vascular endothelial (VE)-cadherin, leading to dissociation of endothelial adherens junctions. A particular tyrosine at position 949 in mouse VEGFR2 has been shown to be required for activation of c-Src. Wild-type mice and mice with phenylalanine replacing tyrosine (Y) 949 in VEGFR2 (Vegfr2Y949F/Y949F ) were challenged with MI through permanent ligation of the left anterior descending coronary artery. The infarct size was similar in wild-type and mutant mice, but left ventricular wall edema and fibrinogen deposition, indicative of vascular leakage, were reduced in the Vegfr2Y949F/Y949F strain. When challenged with large infarcts, the Vegfr2Y949F/Y949F mice survived significantly better than the wild-type strain. Moreover, neutrophil infiltration and levels of myeloperoxidase were low in the infarcted Vegfr2Y949F/Y949F hearts, correlating with improved survival. In vivo tyrosine phosphorylation of VE-cadherin at Y685, implicated in regulation of vascular permeability, was induced by circulating VEGFA in the wild-type but remained at baseline levels in the Vegfr2Y949F/Y949F hearts.Suppression of VEGFA/VEGFR2-regulated vascular permeability leads to diminished edema without affecting vascular density correlating with improved myocardial parameters and survival after MI.
Vascular permeability
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Background: Despite considerable advances in the treatment of myocardial infarction (MI), cardiac rupture remains a devastating complication. We previously showed that growth and differentiation fa...
Cardiac Rupture
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