Involvement of NO and MMPs in microvascular remodeling induced by chronic changes in blood flow

Abstract

Although the role of NO and MMPs in flow (shear stress)-induced remodeling in large compliance arteries is clearly demonstrated, in resistance arteries the mechanism of this remodeling remains mainly unknown and controversial. We submitted mesenteric resistance arteries to chronic increases in blood flow by ligating second order arteries. Arteries submitted to high (HF) were compared to normal flow arteries (NF). Rats were treated with the NO synthase inhibitor L-NAME (60mg/kg) plus the angiotensin converting enzyme inhibitor perindopril (6mg/kg), perindopril (6mg/kg), or the MMPs inhibitor doxycycline (40mg/kg). After 3 weeks, arteries were studied in vitro in an arteriograph. In control rats, diameter increased in HF (438±10.4 at 75 mmHg) compared to NF (340±13.6 at 75 mmHg). In order to get more insight in the mechanism involved in remodeling, we measured in HF and NF arteries, 4 or 14 days after ligation, eNOS expression and MMP-2 and -9 activity and expression using respectively western blot, in situ zymography and immunohistochemistry. Four days after ligation, eNOS expression and MMP activity increased in HF arteries. In addition, L-NAME plus perindopril (used to prevent L-NAME-induced rise in blood pressure) as well as the genetic absence of eNOS in mice, prevented HF remodeling. Perindopril alone did not affect HF remodeling. The role of MMPs in flow-remodeling was confirmed by the use of the MMPs inhibitor doxycycline, which blunted HF remodeling. We conclude that high flow-induced remodeling in resistance arteries involves eNOS overexpression and increased MMP activity, the production of NO and the activity of MMPs being central in this process.