Published online before print December 7, 2006, doi: 10.1161/01.ATV.0000254684.80662.44
© 2007 American Heart Association, Inc.
Vascular Biology |
Key Role of the NO-Pathway and Matrix Metalloprotease-9 in High Blood Flow-Induced Remodeling of Rat Resistance Arteries
From the CNRS UMR 6214; INSERM UMR 771; University of Angers, France.
Correspondence to Dr Daniel Henrion, PharmD, PhD, UMR CNRS 6214 - INSERM 771, Faculté de Médecine, Université d’Angers, 49045 Angers, France. E-mail daniel.henrion{at}univ-angers.fr
Objective— Blood flow is altered in metabolic and ischemic diseases with dramatic consequences. Resistance arteries structure and function remodel in response to chronic blood flow changes through a mechanism remaining mainly unknown. We hypothesized that the NO pathway and matrix metalloproteases (MMPs) activation might play a role in flow (shear stress)-induced microvascular remodeling.
Methods and Results— Mesenteric resistance arteries were ligated to alter blood flow in vivo for 4 or 14 days: arteries were submitted to high (HF), low (LF), or normal flow (NF). Rats were treated with L-NAME, the angiotensin converting enzyme inhibitor perindopril or the MMPs inhibitor doxycycline. After 14 days, outward hypertrophic remodeling occurred in HF arteries in association with eNOS overexpression. MMP9 activity increased in the early phase (day 4). HF-remodeling was prevented by L-NAME, eNOS gene knockout, and doxycycline. L-NAME prevented eNOS overexpression and MMPs activation whereas doxycycline only prevented MMPs activation. In LF arteries diameter reduction was associated with a decreased eNOS expression without change in MMPs expression and activation. LF-remodeling was reduced by perindopril.
Conclusions— In resistance arteries, high flow induced diameter enlargement and wall hypertrophy associated with the sequential activation of eNOS and MMP9.
Blood flow is altered in metabolic and ischemic diseases with dramatic consequences. A chronic increase in blood flow (shear stress) in mesenteric resistance arteries induced outward hypertrophic remodeling attributable to the sequential activation of eNOS and MMP9. Lowering blood flow induced a diameter reduction reflecting the loss of flow-dependent dilation.
Key Words: microcirculation (resistance arteries) • remodeling • blood flow • shear stress • endothelium • nitric oxide • matrix metalloproteases
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