The effects of VEGF-R1 and VEGF-R2 ligands on angiogenic responses and left ventricular function in mice

• Published in: Cardiovascular research Vol. 86; no. 1; pp. 122 - 130
• Main Authors: Huusko, Jenni, Merentie, Mari, Dijkstra, Marike H., Ryhänen, Minttu-Maria, Karvinen, Henna, Rissanen, Tuomas T., Vanwildemeersch, Maarten, Hedman, Marja, Lipponen, Jukka, Heinonen, Suvi E., Eriksson, Ulf, Shibuya, Masabumi, Ylä-Herttuala, Seppo
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-04-2010
• Subjects: Adenoviridae - genetics; Angiogenesis; Animals; Biological and medical sciences; Blotting, Western; Cardiology. Vascular system; Cell Division - drug effects; Cell Division - physiology; Coronary Circulation - drug effects; Coronary Circulation - physiology; Echocardiography; Enzyme-Linked Immunosorbent Assay; Left ventricular function; Ligands; Male; Medical sciences; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Models, Cardiovascular; Mouse myocardium; Myocarditis - chemically induced; Myocarditis - metabolism; Myocarditis - physiopathology; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - physiology; Peptide Fragments - genetics; Peptide Fragments - metabolism; Peptide Fragments - pharmacology; Stroke Volume - drug effects; Stroke Volume - physiology; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor B - genetics; Vascular Endothelial Growth Factor B - metabolism; Vascular Endothelial Growth Factor B - pharmacology; Vascular Endothelial Growth Factor Receptor-1 - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFs; Ventricular Function, Left - drug effects; Ventricular Function, Left - physiology; Viral Proteins - genetics; Viral Proteins - metabolism; Viral Proteins - pharmacology; Mouse myocardium; Ligand; Rodentia; Phlebology; Response; Angiogenesis; Vertebrata; Mammalia; Mouse; Animal; Myocardium; VEGFs; Circulatory system; Cardiology; Left ventricle performance; Left ventricular function
• ISSN: 0008-6363; 1755-3245; 1755-3245
• DOI: 10.1093/cvr/cvp382

Aims Vascular endothelial growth factors (VEGFs) and their receptors (VEGF-Rs) are among the most powerful factors regulating vascular growth. However, it has remained unknown whether stimulation of VEGF-R1, VEGF-R2 or both of the receptors produces the best angiogenic responses in myocardium. The aim of this study was to compare the VEGF-R1-specific ligand VEGF-B186, VEGF-R2-specific ligand VEGF-E and VEGF-A165, which stimulates both receptors, regarding their effects on angiogenesis and left ventricular function in mice. Methods and results High-resolution echocardiography was used to guide the closed-chest injections of adenoviral (Ad) vectors expressing VEGF-B186, VEGF-E, and VEGF-A165 into the anterior wall of the left ventricle in C57Bl/6J mice. Angiogenic and functional effects were analysed using histology, ultrasound and perfusion analyses 6 (D6) and 14 (D14) days after the Ad injection. AdVEGF-A165 induced a strong angiogenic response seen as an enlargement of myocardial capillaries whereas angiogenesis induced by AdVEGF-B186 and AdVEGF-E seemed more physiological. The increase in the capillary area was accompanied with an increase in myocardial perfusion at D6 after the gene injection. AdVEGF-A165 and AdVEGF-E induced endothelial-specific proliferation whereas AdVEGF-B186 mostly induced proliferation of cardiomyocytes. AdVEGF-A165 induced more pronounced tissue damage than AdVEGF-B186 and AdVEGF-E. Left ventricular function measured as ejection fraction did not change during the follow-up. AdVEGF-A165 increased both VEGF-R1 and VEGF-R2 protein expression whereas AdVEGF-B186 and AdVEGF-E did not affect endogenous receptor expression levels. Conclusion AdVEGF-B186 and AdVEGF-E are equally potent in inducing therapeutic angiogenesis in mouse myocardium and produce less side effects than AdVEGF-A165.