title: Vascular endothelial growth factor-B gene transfer prevents angiotensin II-induced diastolic dysfunction via proliferation and capillary dilatation in rats.
abstract: OBJECTIVE
  heart growth and function are angiogenesis-dependent, but little is known concerning the effects of key regulators of angiogenesis on diastolic heart failure. Here, we tested the hypothesis that local vascular endothelial growth factor-B (VEGF-B) gene therapy prevents left ventricular diastolic dysfunction.
  
  
  RESULTS
  rats were subjected to pressure overload by infusing angiotensin II (33.3 microg/kg/h) for 2 weeks using osmotic minipumps. Intramyocardial delivery of adenoviral vector expressing VEGF-B(167A) improved the angiotensin II-induced diastolic dysfunction compared with LacZ control virus. Local VEGF-B gene transfer increased the mean capillary area in the left ventricle in control and angiotensin II-infused animals, whereas the density of capillaries was not affected. Interestingly, significant increases were noted in Ki67(+) proliferating cells, expression of interleukin1β, and c-kit(+) cells in response to VEGF-B gene transfer. The increase in cardiac c-kit(+) cells was not associated with an induction of stromal cell-derived factor 1α, suggesting no mobilization of cells from bone marrow. Also, the phosphatidylinositol 3-kinase/Akt pathway was activated.
  
  
  CONCLUSIONS
  VEGF-B gene transfer resulted in prevention of the angiotensin II-induced diastolic dysfunction associated with induction of the Akt pathway, increased proliferation and number of c-kit(+) cells, as well as an increase in the capillary area in the left ventricle. VEGF-B may offer novel therapeutic possibilities for the prevention of the transition from compensated to decompensated cardiac hypertrophy and thereby for the treatment of heart failure.
authors: Department of Pharmacology and Toxicology, Biocenter Oulu, Institute of Biomedicine, University of Oulu, P.O. Box 5000, 90014 Oulu, Finland.
authors: Raisa
authors: R
authors: Serpi
authors: Anna-Maria
authors: AM
authors: Tolonen
authors: Jenni
authors: J
authors: Huusko
authors: Jaana
authors: J
authors: Rysä
authors: Olli
authors: O
authors: Tenhunen
authors: Seppo
authors: S
authors: Ylä-Herttuala
authors: Heikki
authors: H
authors: Ruskoaho
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D002196:Capillaries / Q000473:pathology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005355:Fibrosis; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D054144:Heart Failure, Diastolic / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006801:Humans; D032383:Myocytes, Cardiac / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D042561:Vascular Endothelial Growth Factor B / Q000235:genetics* / Q000502:physiology / Q000627:therapeutic use
chemical_list: D012333:RNA, Messenger; D011994:Recombinant Proteins; C467485:VEGFB protein, human; C581256:VEGFB protein, rat; D042561:Vascular Endothelial Growth Factor B; D000804:Angiotensin II; D019009:Proto-Oncogene Proteins c-kit; D051057:Proto-Oncogene Proteins c-akt