title: Vascular endothelial growth factor delays onset of failure in pressure-overload hypertrophy through matrix metalloproteinase activation and angiogenesis.
abstract: OBJECTIVE
  Pressure-overload hypertrophy is associated with decreased capillary density in myocardium resulting in impaired substrate delivery. Treatment of hypertrophied hearts with vascular endothelial growth factor (VEGF) induces angiogenesis. Since angiogenesis is associated with extracellular matrix degradation, we sought to determine whether VEGF induced angiogenesis in hypertrophy required matrix metalloproteinases (MMP) activation.
  
  
  METHODS
  Newborn rabbits underwent aortic banding. Progression of hypertrophy (mass-to-volume (M/V) ratio) and mid-wall contractility index was monitored by echocardiography. At 4 and 6 weeks, VEGF (2 microg/kg), vehicle or VEGF combined with GM6001 (5 mg/kg), a MMP inhibitor, was administered intrapericardially. CD-31 (indicator of angiogenesis), MMP-2, MT1-MMP and TIMPs (endogenous MMP inhibitors) expression were measured by immunoblotting. MMP-2 activity was determined by gelatin zymography.
  
  
  RESULTS
  Untreated hypertrophied hearts progressed to ventricular dilatation at 7 wks (M/V ratio: 0.75 +/- 0.07), but compensatory hypertrophy was maintained with VEGF (0.91 +/- 0.07; p < 0.05). LV contractility declined in untreated hearts from -0.41 +/- 0.9 (5 wks) to -0.73 +/- 0.5 (7 wks; p < 0.05) but remained normal with VEGF (+1.61 +/- 0.6 vs. +0.47 +/- 0.2). MMP-2 expression and activity were significantly elevated in VEGF treated hypertrophied hearts (p < 0.05) and were blocked by concomitant administration of GM6001. VEGF induced neovascularization was inhibited by addition of GM6001. MT1-MMP showed a trend to higher levels in VEGF treated hearts. TIMPs were unchanged in all three groups.
  
  
  CONCLUSIONS
  Exogenous VEGF and resultant MMP-2 activation leads to increased capillary formation in severe hypertrophy, preventing progression to ventricular dilation and dysfunction. VEGF and the associated MMP-2 activation play an important and potentially therapeutic role in vascular remodeling of hypertrophied hearts.
authors.affiliation: Department of Cardiac Surgery, Children's Hospital Boston, Harvard Medical School, 300 Longwood Ave., BADER 279, Boston, MA 02115, USA.
authors.forename: I
authors.initials: I
authors.lastname: Friehs
authors.forename: R E
authors.initials: RE
authors.lastname: Margossian
authors.forename: A M
authors.initials: AM
authors.lastname: Moran
authors.forename: H
authors.initials: H
authors.lastname: Cao-Danh
authors.forename: M A
authors.initials: MA
authors.lastname: Moses
authors.forename: P J
authors.initials: PJ
authors.lastname: del Nido
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002303:Cardiac Output, Low / Q000517:prevention & control*; D003331:Coronary Vessels / Q000187:drug effects*; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004452:Echocardiography; D004789:Enzyme Activation / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015151:Immunoblotting; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology; D011817:Rabbits; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology* / Q000627:therapeutic use; D017725:Ventricular Pressure / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D043925:Angiogenesis Inducing Agents; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D042461:Vascular Endothelial Growth Factor A; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D053511:Matrix Metalloproteinase 14