on December 7, 2006
Published online before print December 7, 2006, doi: 10.1161/01.ATV.0000254684.80662.44
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Submitted on April 27, 2006
Accepted on November 9, 2006
Key Role of the NO-Pathway and Matrix Metalloprotease-9 in High Blood Flow-Induced Remodeling of Rat Resistance Arteries
Odile Dumont ;
From the CNRS UMR 6214, INSERM UMR 771, University of Angers, France.
* To whom correspondence should be addressed. 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.
Key words: microcirculation (resistance arteries) • remodeling • blood flow • shear stress • endothelium • nitric oxide • matrix metalloproteases
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