The effects of VEGF-R1 and VEGF-R2 ligands on angiogenic responses and left ventricular function in mice.
OBJECTIVE
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-B(186), VEGF-R2-specific ligand VEGF-E and VEGF-A(165,) which stimulates both receptors, regarding their effects on angiogenesis and left ventricular function in mice.


RESULTS
High-resolution echocardiography was used to guide the closed-chest injections of adenoviral (Ad) vectors expressing VEGF-B(186,) VEGF-E, and VEGF-A(165) 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-A(165) induced a strong angiogenic response seen as an enlargement of myocardial capillaries whereas angiogenesis induced by AdVEGF-B(186) 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-A(165) and AdVEGF-E induced endothelial-specific proliferation whereas AdVEGF-B(186) mostly induced proliferation of cardiomyocytes. AdVEGF-A(165) induced more pronounced tissue damage than AdVEGF-B(186) and AdVEGF-E. Left ventricular function measured as ejection fraction did not change during the follow-up. AdVEGF-A(165) increased both VEGF-R1 and VEGF-R2 protein expression whereas AdVEGF-B(186) and AdVEGF-E did not affect endogenous receptor expression levels.


CONCLUSIONS
AdVEGF-B(186) and AdVEGF-E are equally potent in inducing therapeutic angiogenesis in mouse myocardium and produce less side effects than AdVEGF-A(165).
Huusko
Jenni
J
Department of Biotechnology and Molecular Medicine, AI Virtanen Institute for Molecular Sciences, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland.
Merentie
Mari
M
Dijkstra
Marike H
MH
Ryhänen
Minttu-Maria
MM
Karvinen
Henna
H
Rissanen
Tuomas T
TT
Vanwildemeersch
Maarten
M
Hedman
Marja
M
Lipponen
Jukka
J
Heinonen
Suvi E
SE
Eriksson
Ulf
U
Shibuya
Masabumi
M
Ylä-Herttuala
Seppo
S
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008955:Models, Cardiovascular; D009205:Myocarditis / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology
D008024:Ligands; D010446:Peptide Fragments; C084758:VEGF-like protein, Orf virus; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D014764:Viral Proteins; C511613:vascular endothelial growth factor A (138-165); D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2