title: Tissue inhibition of angiotensin-converting enzyme activity stimulates angiogenesis in vivo.
abstract: BACKGROUND
  Endothelial cells (ECs) represent the critical cellular element responsible for postnatal angiogenesis. Because ACE inhibitors may favorably affect endothelial function, we investigated the hypothesis that administration of the ACE inhibitor quinaprilat could enhance angiogenesis in vivo.
  
  
  RESULTS
  Ten days after resection of 1 femoral artery, New Zealand White (NZW) rabbits were randomly assigned to receive recombinant human vascular endothelial growth factor (rhVEGF) administered as a single intra-arterial injection (n=6), quinaprilat (n=8) or captopril (n=7) administered as a daily subcutaneous injection, or no treatment (controls, n=6). Angiogenesis was monitored in vivo by measurement of blood pressure, vasoreactivity, and resistance in ischemic versus normal limbs at day 10 (D10) and D40; angiographic studies to identify sites of neovascularization were performed at D10 and D40, and morphometric analysis of capillary density in the ischemic limb was performed at necropsy (D40). Both functional and morphological outcomes documented augmented angiogenesis in quinaprilat-treated rabbits similar to that observed for rhVEGF and superior to that observed with either captopril or no drug (controls). Residual ACE activity was equivalent for the captopril and quinaprilat groups in plasma (42.54+/-0.03% versus 41.53+/-0.02%, P=NS) but not in tissue, where quinaprilat lowered ACE activity significantly (P<0.01) compared with captopril (13% versus 61%).
  
  
  CONCLUSIONS
  ACE inhibition with quinaprilat promotes angiogenesis in a rabbit model of hindlimb ischemia. Thus, nonsulfhydryl ACE inhibitors with high tissue affinity may be potentially useful for therapeutic angiogenesis in ischemic tissues. Moreover, previous evidence that ACE inhibition benefits patients with myocardial ischemia may be due in part to augmented collateral development.
authors.affiliation: Departments of Medicine (Vascular Medicine) and Biomedical Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, MA, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Fabre
authors.forename: A
authors.initials: A
authors.lastname: Rivard
authors.forename: M
authors.initials: M
authors.lastname: Magner
authors.forename: M
authors.initials: M
authors.lastname: Silver
authors.forename: J M
authors.initials: JM
authors.lastname: Isner
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology*; D017536:Carotid Artery, Common / Q000187:drug effects / Q000502:physiology; D016228:Endothelial Growth Factors / Q000494:pharmacology*; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects*; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008222:Lymphokines / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D007703:Peptidyl-Dipeptidase A / Q000097:blood*; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D044005:Tetrahydroisoquinolines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D016228:Endothelial Growth Factors; D007546:Isoquinolines; D008222:Lymphokines; D011994:Recombinant Proteins; D044005:Tetrahydroisoquinolines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C054501:quinaprilat; D002216:Captopril; D007703:Peptidyl-Dipeptidase A