Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart

Abstract

VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac-specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis.

Microvascular Notch Signaling Is Upregulated in Response to Vascular Endothelial Growth Factor and Chronic Myocardial Ischemia

“…Increased expression of VEGF and Angiopoietin-1 has been shown to improve perfusion by inducing angiogenesis and myocardial proliferation in a porcine model of myocardial infarction. 27 In the current study, Angiopoietin-1 was more highly expressed in the VEGF-treated animals as well.…”

MicroRNAs in the Myocyte Enhancer Factor 2 (MEF2)-regulated Gtl2-Dio3 Noncoding RNA Locus Promote Cardiomyocyte Proliferation by Targeting the Transcriptional Coactivator Cited2

“…We also examined the expression of Vegfa because previous studies have shown that the Vegf promoter is repressed by Cited2 (34). In addition, delivery of VEGF to the injured heart has been shown to induce cardiomyocyte proliferation (35,36). As shown in Fig.…”

Candesartan Induces a Prolonged Proangiogenic Effect and Augments Endothelium-Mediated Neuroprotection after Oxygen and Glucose Deprivation: Role of Vascular Endothelial Growth Factors A and B

“…Ang-1 expression falls dramatically after focal cerebral ischemia, resulting in a leaky blood-brain barrier. Increases in Ang-1 levels, however, preserve vascular integrity after focal ischemia and/or VEGF administration (Thurston et al, 2000;Tao et al, 2011). The use of the aforementioned angiogenic and vascular protective factors might seem to be a promising treatment of acute ischemic stroke.…”