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VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart.

ABSTRACT: Angiogenic growth factors have recently been linked to tissue metabolism. We have used genetic gain- and loss-of function models to elucidate the effects and mechanisms of action of vascular endothelial growth factor-B (VEGF-B) in the heart. A cardiomyocyte-specific VEGF-B transgene induced an expanded coronary arterial tree and reprogramming of cardiomyocyte metabolism. This was associated with protection against myocardial infarction and preservation of mitochondrial complex I function upon ischemia-reperfusion. VEGF-B increased VEGF signals via VEGF receptor-2 to activate Erk1/2, which resulted in vascular growth. Akt and mTORC1 pathways were upregulated and AMPK downregulated, readjusting cardiomyocyte metabolic pathways to favor glucose oxidation and macromolecular biosynthesis. However, contrasting with a previous theory, there was no difference in fatty acid uptake by the heart between the VEGF-B transgenic, gene-targeted or wildtype rats. Importantly, we also show that VEGF-B expression is reduced in human heart disease. Our data indicate that VEGF-B could be used to increase the coronary vasculature and to reprogram myocardial metabolism to improve cardiac function in ischemic heart disease.

SUBMITTER: Kivela R

PROVIDER: S-EPMC3958306 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart.

Kivelä Riikka R Bry Maija M Robciuc Marius R MR Räsänen Markus M Taavitsainen Miia M Silvola Johanna M U JM Saraste Antti A Hulmi Juha J JJ Anisimov Andrey A Mäyränpää Mikko I MI Lindeman Jan H JH Eklund Lauri L Hellberg Sanna S Hlushchuk Ruslan R Zhuang Zhen W ZW Simons Michael M Djonov Valentin V Knuuti Juhani J Mervaala Eero E Alitalo Kari K

EMBO molecular medicine 20140121 3

Angiogenic growth factors have recently been linked to tissue metabolism. We have used genetic gain- and loss-of function models to elucidate the effects and mechanisms of action of vascular endothelial growth factor-B (VEGF-B) in the heart. A cardiomyocyte-specific VEGF-B transgene induced an expanded coronary arterial tree and reprogramming of cardiomyocyte metabolism. This was associated with protection against myocardial infarction and preservation of mitochondrial complex I function upon is ...[more]

PMID: 24448490

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Project description:Recently, vascular endothelial growth factor-C (VEGF-C or VEGF-2) was described as a specific ligand for the endothelial receptor tyrosine kinases VEGFR-2 and VEGFR-3. In vivo data, limited to constitutive overexpression in transgenic mice, have been interpreted as evidence that the growth-promoting effects of VEGF-C are restricted to development of the lymphatic vasculature. The current studies were designed to test the hypothesis that constitutive expression of VEGF-C in adult animals promotes angiogenesis. In vitro, VEGF-C exhibited a dose-dependent mitogenic and chemotactic effect on endothelial cells, particularly for microvascular endothelial cells (72% and 95% potency, respectively, compared with VEGF-A/VEGF-1). VEGF-C stimulated release of nitric oxide from endothelial cells and increased vascular permeability in the Miles assay; the latter effect was attenuated by pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester. Both VEGFR-2 and VEGFR-3 receptors were shown to be expressed in human saphenous vein and internal mammary artery. The potential for VEGF-C to promote angiogenesis in vivo was then tested in a rabbit ischemic hindlimb model. Ten days after ligation of the external iliac artery, VEGF-C was administered as naked plasmid DNA (pcVEGF-C; 500 microg) from the polymer coating of an angioplasty balloon (n = 8 each) or as recombinant human protein (rhVEGF-C; 500 microg) by direct intra-arterial infusion. Physiological and anatomical assessments of angiogenesis 30 days later showed evidence of therapeutic angiogenesis for both pcVEGF-C and rhVEGF-C. Hindlimb blood pressure ratio (ischemic/normal) after pcVEGF-C increased to 0.83 +/- 0.03 after pcVEGF-C versus 0.59 +/- 0.04 (P < 0.005) in pGSVLacZ controls and to 0.76 +/- 0.04 after rhVEGF-C versus 0.58 +/- 0.03 (P < 0.01) in control rabbits receiving rabbit serum albumin. Doppler-derived iliac flow reserve was 2.7 +/- 0.1 versus 2.0 +/- 0.2 (P < 0.05) for pcVEGF-C versus LacZ controls and 2.9 +/- 0.3 versus 2.1 +/- 0.2 (P < 0.05) for rhVEGF-C versus albumin controls. Neovascularity was documented by angiography in vivo (angiographic scores: 0.85 +/- 0.05 versus 0.51 +/- 0.02 (P < 0.001) for plasmid DNA and 0.74 +/- 0.08 versus 0.53 +/- 0.03 (P < 0.05) for protein), and capillary density (per mm2) was measured at necropsy (252 +/- 12 versus 183 +/- 10 (P < 0.005) for plasmid DNA and 229 +/- 20 versus 164 +/- 20 (P < 0.05) for protein). In contrast to the results of gene targeting experiments, constitutive expression of VEGF-C in adult animals promotes angiogenesis in the setting of limb ischemia. VEGF-C and its receptors thus constitute an apparently redundant pathway for postnatal angiogenesis and may represent an alternative to VEGF-A for strategies of therapeutic angiogenesis in patients with limb and/or myocardial ischemia.

Project description:Background and purposeBrain edema is an important underlying pathology in acute stroke, especially when comorbidities are present. VEGF (Vascular endothelial growth factor) signaling is implicated in edema. This study investigated whether obesity impacts VEGF signaling and brain edema, as well as whether VEGF inhibition alters stroke outcome in obese subjects.MethodsHigh-fat diet-induced obese mice were subjected to a transient middle cerebral artery occlusion. VEGF-A and VEGFR2 (receptor) expression, infarct volume, and swelling were measured 3 days post-middle cerebral artery occlusion. To validate the effect of an anti-VEGF strategy, we used aflibercept, a fusion protein that has a VEGF-binding domain and acts as a decoy receptor, in human umbilical vein endothelial cells stimulated with rVEGF (recombinant VEGF; 50 ng/mL) for permeability and tube formation. In vivo, aflibercept (10 mg/kg) or IgG control was administered in obese mice 3 hours after transient 30 minutes middle cerebral artery occlusion. Blood-brain barrier integrity was assessed by IgG staining and dextran extravasation in the postischemic brain. A separate cohort of nonobese (lean) mice was subjected to 40 minutes middle cerebral artery occlusion to test the effect of aflibercept on malignant infarction.ResultsCompared with lean mice, obese mice had increased mortality, infarct volume, swelling, and blood-brain barrier disruption. These outcomes were also associated with increased VEGF-A and VEGFR2 expression. Aflibercept reduced VEGF-A-stimulated permeability and tube formation in human umbilical vein endothelial cells. Compared with the IgG-treated controls, mice treated with aflibercept had reduced mortality rates (40% versus 17%), hemorrhagic transformation (43% versus 27%), and brain swelling (28% versus 18%), although the infarct size was similar. In nonobese mice with large stroke, aflibercept neither improved nor exacerbated stroke outcomes.ConclusionsThe study demonstrates that aflibercept selectively attenuates stroke-induced brain edema and vascular permeability in obese mice. These findings suggest the repurposing of aflibercept to reduce obesity-enhanced brain edema in acute stroke.

Dataset Information

VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart.

Publications

VEGF-B-induced vascular growth leads to metabolic reprogramming and ischemia resistance in the heart.

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