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Myocardial infarction stabilization by cell-based expression of controlled Vascular Endothelial Growth Factor levels.

ABSTRACT: Vascular Endothelial Growth Factor (VEGF) can induce normal or aberrant angiogenesis depending on the amount secreted in the microenvironment around each cell. Towards a possible clinical translation, we developed a Fluorescence Activated Cell Sorting (FACS)-based technique to rapidly purify transduced progenitors that homogeneously express a desired specific VEGF level from heterogeneous primary populations. Here, we sought to induce safe and functional angiogenesis in ischaemic myocardium by cell-based expression of controlled VEGF levels. Human adipose stromal cells (ASC) were transduced with retroviral vectors and FACS purified to generate two populations producing similar total VEGF doses, but with different distributions: one with cells homogeneously producing a specific VEGF level (SPEC), and one with cells heterogeneously producing widespread VEGF levels (ALL), but with an average similar to that of the SPEC population. A total of 70 nude rats underwent myocardial infarction by coronary artery ligation and 2 weeks later VEGF-expressing or control cells, or saline were injected at the infarction border. Four weeks later, ventricular ejection fraction was significantly worsened with all treatments except for SPEC cells. Further, only SPEC cells significantly increased the density of homogeneously normal and mature microvascular networks. This was accompanied by a positive remodelling effect, with significantly reduced fibrosis in the infarcted area. We conclude that controlled homogeneous VEGF delivery by FACS-purified transduced ASC is a promising strategy to achieve safe and functional angiogenesis in myocardial ischaemia.

SUBMITTER: Melly L

PROVIDER: S-EPMC5908097 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Myocardial infarction stabilization by cell-based expression of controlled Vascular Endothelial Growth Factor levels.

Melly Ludovic L Cerino Giulia G Frobert Aurélien A Cook Stéphane S Giraud Marie-Noëlle MN Carrel Thierry T Tevaearai Stahel Hendrik T HT Eckstein Friedrich F Rondelet Benoît B Marsano Anna A Banfi Andrea A

Journal of cellular and molecular medicine 20180225 5

Vascular Endothelial Growth Factor (VEGF) can induce normal or aberrant angiogenesis depending on the amount secreted in the microenvironment around each cell. Towards a possible clinical translation, we developed a Fluorescence Activated Cell Sorting (FACS)-based technique to rapidly purify transduced progenitors that homogeneously express a desired specific VEGF level from heterogeneous primary populations. Here, we sought to induce safe and functional angiogenesis in ischaemic myocardium by c ...[more]

PMID: 29478261

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Project description:BackgroundSecretoneurin is a neuropeptide located in nerve fibers along blood vessels, is upregulated by hypoxia, and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells.Methods and resultsIn vivo secretoneurin improved left ventricular function, inhibited remodeling, and reduced scar formation. In the infarct border zone, secretoneurin induced coronary angiogenesis, as shown by increased density of capillaries and arteries. In vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis, and activated Akt and extracellular signal-regulated kinase in coronary endothelial cells. Effects were abrogated by a vascular endothelial growth factor (VEGF) antibody, and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells, and binding was blocked by heparinase, indicating that secretoneurin stimulates binding of VEGF to heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its coreceptor neuropilin-1. In endothelial cells, secretoneurin also stimulated fibroblast growth factor receptor-3 and insulin-like growth factor-1 receptor, and in coronary vascular smooth muscle cells, we observed stimulation of VEGF receptor-1 and fibroblast growth factor receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin messenger RNA and protein.ConclusionsOur data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low-affinity binding sites and neuropilin-1 and stimulates further growth factor receptors like fibroblast growth factor receptor-3. Our in vivo findings indicate that secretoneurin may be a promising therapeutic tool in ischemic heart disease.

Project description:BackgroundSeveral clinical studies have suggested that the early administration of statins could reduce the risk of in-hospital mortality in acute myocardial infarction (AMI) patients. Recently, some studies have identified that stimulating lymphangiogenesis after AMI could improve cardiac function by reducing myocardial edema and inflammation. This study aimed to identify the effect of rosuvastatin on postinfarct lymphangiogenesis and to identify the underlying mechanism of this effect.MethodMyocardial infarction (MI) was induced by ligation of the left anterior descending coronary artery in mice orally administered rosuvastatin for 7 days. The changes in cardiac function, pathology, and lymphangiogenesis following MI were measured by echocardiography and immunostaining. EdU, Matrigel tube formation, and scratch wound assays were used to evaluate the effect of rosuvastatin on the proliferation, tube formation, and migration of the lymphatic endothelial cell line SVEC4-10. The expression of miR-107-3p, miR-491-5p, and VEGFR3 was measured by polymerase chain reaction (PCR) and Western blotting. A gain-of-function study was performed using miR-107-3p and miR-491-5p mimics.ResultsThe rosuvastatin-treated mice had a significantly improved ejection fraction and increased lymphatic plexus density 7 days after MI. Rosuvastatin also reduced myocardial edema and inflammatory response after MI. We used a VEGFR3 inhibitor to partially reverse these effects. Rosuvastatin promoted the proliferation, migration, and tube formation of SVEC4-10 cells. PCR and Western blot analyses revealed that rosuvastatin intervention downregulated miR-107-3p and miR-491-5p and promoted VEGFR3 expression. The gain-of-function study showed that miR-107-3p and miR-491-5p could inhibit the proliferation, migration, and tube formation of SVEC4-10 cells.ConclusionRosuvastatin could improve heart function by promoting lymphangiogenesis after MI by regulating the miRNAs/VEGFR3 pathway.

Project description:PurposeTo assess the effect of availability of anti-vascular endothelial growth factor (VEGF) therapy on mortality and hospitalizations for acute myocardial infarction (AMI) and stroke over a 5-year follow-up period in United States Medicare beneficiaries newly diagnosed with exudative age-related macular degeneration (AMD) in 2006 compared with control groups consisting of beneficiaries (1) newly diagnosed with exudative AMD at a time when anti-VEGF therapy was not possible and (2) newly diagnosed with nonexudative AMD.DesignRetrospective cohort study.ParticipantsBeneficiaries newly diagnosed with exudative and nonexudative AMD in 2000 and 2006 selected from a random longitudinal sample of Medicare 5% claims and enrollment files.MethodsBeneficiaries with a first diagnosis of exudative AMD in 2006 were the treatment group; beneficiaries newly diagnosed with exudative AMD in 2000 or nonexudative AMD in 2000 or 2006 were control groups. To deal with potential selection bias, we designed an intent-to-treat study, which controlled for nonadherence to prescribed regimens. The treatment group consisted of patients with clinically appropriate characteristics to receive anti-VEGF injections given that the therapy is available, bypassing the need to monitor whether treatment was actually received. Control groups consisted of patients with clinically appropriate characteristics but first diagnosed at a time when the therapy was unavailable (2000) and similar patients but for whom the therapy was not clinically indicated (2000, 2006). We used a Cox proportional hazard model.Main outcome measuresAll-cause mortality and hospitalization for AMI and stroke during follow-up.ResultsNo statistically significant changes in probabilities of death and hospitalizations for AMI and stroke within a 5-year follow-up period were identified in exudative AMD beneficiaries newly diagnosed in 2006, the beginning of widespread anti-VEGF use, compared with 2000. As an alternative to our main analysis, which excluded beneficiaries from nonexudative AMD group who received anti-VEGF therapies during follow-up, we performed a sensitivity analysis with this group of individuals reincluded (11% of beneficiaries newly diagnosed with nonexudative AMD in 2006). Results were similar.ConclusionsIntroduction of anti-VEGF agents in 2006 for treating exudative AMD has not posed a threat of increased risk of AMI, stroke, or all-cause mortality.

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Myocardial infarction stabilization by cell-based expression of controlled Vascular Endothelial Growth Factor levels.

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Myocardial infarction stabilization by cell-based expression of controlled Vascular Endothelial Growth Factor levels.

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