title: AAV9-mediated VEGF-B gene transfer improves systolic function in progressive left ventricular hypertrophy.
abstract: Mechanisms of the transition from compensatory hypertrophy to heart failure are poorly understood and the roles of vascular endothelial growth factors (VEGFs) in this process have not been fully clarified. We determined the expression profile of VEGFs and relevant receptors during the progression of left ventricular hypertrophy (LVH). C57BL mice were exposed to transversal aortic constriction (TAC) and the outcome was studied at different time points (1 day, 2, 4, and 10 weeks). A clear compensatory phase (2 weeks after TAC) was seen with following heart failure (4 weeks after TAC). Interestingly, VEGF-C and VEGF-D as well as VEGF receptor-3 (VEGFR-3) were upregulated in the compensatory hypertrophy and VEGF-B was downregulated in the heart failure. After treatment with adeno-associated virus serotype 9 (AAV9)-VEGF-B(186) gene therapy in the compensatory phase for 4 weeks the function of the heart was preserved due to angiogenesis, inhibition of apoptosis, and promotion of cardiomyocyte proliferation. Also, the genetic programming towards fetal gene expression, a known phenomenon in heart failure, was partly reversed in AAV9-VEGF-B(186)-treated mice. We conclude that VEGF-C and VEGF-D are associated with the compensatory LVH and that AAV9-VEGF-B(186) gene transfer can rescue the function of the failing heart and postpone the transition towards heart failure.
authors.affiliation: Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Huusko
authors.forename: Line
authors.initials: L
authors.lastname: Lottonen
authors.forename: Mari
authors.initials: M
authors.lastname: Merentie
authors.forename: Erika
authors.initials: E
authors.lastname: Gurzeler
authors.forename: Andrey
authors.initials: A
authors.lastname: Anisimov
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyanohara
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Pasi
authors.initials: P
authors.lastname: Tavi
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004452:Echocardiography; D017379:Hypertrophy, Left Ventricular / Q000503:physiopathology / Q000628:therapy*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics / Q000378:metabolism*
chemical_list: D042561:Vascular Endothelial Growth Factor B