title: Myocardial hypertrophy overrides the angiogenic response to hypoxia.
abstract: BACKGROUND
  Cyanosis and myocardial hypertrophy frequently occur in combination. Hypoxia or cyanosis can be potent inducers of angiogenesis, regulating the expression of hypoxia-inducible factors (HIF), vascular endothelial growth factors (VEGF), and VEGF receptors (VEGFR-1 and 2); in contrast, pressure overload hypertrophy is often associated with impaired pro-angiogenic signaling and decreased myocardial capillary density. We hypothesized that the physiological pro-angiogenic response to cyanosis in the hypertrophied myocardium is blunted through differential HIF and VEGF-associated signaling.
  
  
  RESULTS
  Newborn rabbits underwent aortic banding and, together with sham-operated littermates, were transferred into a hypoxic chamber (FiO(2) = 0.12) at 3 weeks of age. Control banded or sham-operated rabbits were housed in normoxia. Systemic cyanosis was confirmed (hematocrit, arterial oxygen saturation, and serum erythropoietin). Myocardial tissue was assayed for low oxygen concentrations using a pimonidazole adduct. At 4 weeks of age, HIF-1alpha and HIF-2alpha protein levels, HIF-1alpha DNA-binding activity, and expression of VEGFR-1, VEGFR-2, and VEGF were determined in hypoxic and normoxic rabbits. At 6 weeks of age, left-ventricular capillary density was assessed by immunohistochemistry. Under normoxia, capillary density was decreased in the banded rabbits compared to non-banded littermates. As expected, non-hypertrophied hearts responded to hypoxia with increased capillary density; however, banded hypoxic rabbits demonstrated no increase in angiogenesis. This blunted pro-angiogenic response to hypoxia in the hypertrophied myocardium was associated with lower HIF-2alpha and VEGFR-2 levels and increased HIF-1alpha activity and VEGFR-1 expression. In contrast, non-hypertrophied hearts responded to hypoxia with increased HIF-2alpha and VEGFR-2 expression with lower VEGFR-1 expression.
  
  
  CONCLUSIONS
  The participation of HIF-2alpha and VEGFR-2 appear to be required for hypoxia-stimulated myocardial angiogenesis. In infant rabbit hearts with pressure overload hypertrophy, this pro-angiogenic response to hypoxia is effectively uncoupled, apparently in part due to altered HIF-mediated signaling and VEGFR subtype expression.
authors.affiliation: Department of Cardiac Surgery, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, USA. yh.choi@uk-koeln.de
authors.forename: Yeong-Hoon
authors.initials: YH
authors.lastname: Choi
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cowan
authors.forename: Meena
authors.initials: M
authors.lastname: Nathan
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Poutias
authors.forename: Christof
authors.initials: C
authors.lastname: Stamm
authors.forename: Pedro J
authors.initials: PJ
authors.lastname: del Nido
authors.forename: Francis X
authors.initials: FX
authors.lastname: McGowan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002196:Capillaries / Q000473:pathology; D005786:Gene Expression Regulation; D006984:Hypertrophy; D000860:Hypoxia; D008954:Models, Biological; D009206:Myocardium / Q000473:pathology*; D009389:Neovascularization, Pathologic; D011817:Rabbits; D014157:Transcription Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099162:Endothelial PAS Domain-Containing Protein 1