Key role of the NO-pathway and matrix metalloprotease-9 in high blood flow-induced remodeling of rat resistance arteries.
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.


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.
Dumont
Odile
O
UMR CNRS 6214-INSERM 771, Faculté de Médecine, Université d'Angers, 49045 Angers, France.
Loufrani
Laurent
L
Henrion
Daniel
D
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D004318:Doxycycline / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006984:Hypertrophy; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008638:Mesenteric Arteries / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D020913:Perindopril / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D014655:Vascular Resistance / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects
D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline; D019331:NG-Nitroarginine Methyl Ester; D020913:Perindopril