title: Direct renin inhibition with aliskiren improves ischemia-induced neovascularization: blood pressure-independent effect.
abstract: BACKGROUND
  Renin is the rate limiting step for the activation of the renin-angiotensin-aldosterone system, which is linked to the development of endothelial dysfunction, hypertension and atherosclerosis. However, the specific role of renin during physiological responses to tissue ischemia is currently unknown. Aliskiren is the only direct renin inhibitor that is clinically used as an orally active antihypertensive drug. Here we tested the hypothesis that aliskiren might improve neovascularization in response to ischemia.
  
  
  RESULTS
  At a dose that did not modulate blood pressure (10 mg/kg), aliskiren led to improved blood flow recovery after hindlimb ischemia in C57BL/6 mice (Doppler flow ratios 0.71 ± 0.07 vs. 0.55 ± 0.03; P < 0.05). In ischemic muscles, treatment with aliskiren was associated with a significant increase of vascular density, reduced oxidative stress levels and increased expression of VEGF and eNOS. Aliskiren treatment also significantly increased the number of bone marrow-derived endothelial progenitor cells (EPCs) after hindlimb ischemia. Moreover, the angiogenic properties of EPCs (migration, adhesion, integration into tubules) were significantly improved in mice treated with aliskiren. In vitro, aliskiren improves cellular migration and tubule formation in HUVECs. This is associated with an increased expression of nitric oxide (NO), and a significant reduction of oxidative stress levels. Importantly, the angiogenic properties of aliskiren in vitro and in vivo are completely abolished following treatment with the NOS inhibitor l-NAME.
  
  
  CONCLUSIONS
  Direct renin inhibition with aliskiren leads to improved ischemia-induced neovascularization that is not dependant on blood pressure lowering. The mechanism involves beneficial effects of aliskiren on oxidative stress and NO angiogenic pathway, together with an increase in the number and the functional activities of EPCs.
authors: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Michel
authors: M
authors: Desjarlais
authors: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Sylvie
authors: S
authors: Dussault
authors: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Wahiba
authors: W
authors: Dhahri
authors: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors: Raphael
authors: R
authors: Mathieu
authors: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada. Electronic address: alain.rivard@umontreal.ca.
authors: Alain
authors: A
authors: Rivard
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry; D001794:Blood Pressure / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology; D002448:Cell Adhesion; D002465:Cell Movement; D042783:Endothelial Cells / Q000166:cytology; D066026:Endothelial Progenitor Cells / Q000166:cytology; D005650:Fumarates / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D007511:Ischemia / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019331:NG-Nitroarginine Methyl Ester / Q000737:chemistry; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000737:chemistry; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D017382:Reactive Oxygen Species; D012084:Renin-Angiotensin System / Q000187:drug effects; D013481:Superoxides / Q000737:chemistry; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D005650:Fumarates; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D010100:Oxygen; D017382:Reactive Oxygen Species; D013481:Superoxides; D000092502:Renin Inhibitors; C446481:aliskiren
keywords: Aliskiren; Angiogenesis; Endothelial progenitor cells; Neovascularization; Nitric oxide; Oxidative stress; Renin