Mice lacking the gene encoding for MMP-9 and resistance artery reactivity

ObjectivesTo define the link between the deletion of gene encoding for metalloproteinase 9 and resistance artery reactivity, we studied in vitro smooth muscle and endothelial cell function in response to pressure, shear stress, and pharmacological agents.BackgroundMatrix metalloproteinases play a crucial role in the regulation of extracellular matrix turnover and structural artery wall remodeling.MethodsResistance arteries were isolated from mice lacking gene encoding for MMP-9 (KO) and their control (WT). Hemodynamic, pharmacology approaches, and Western blot analysis were used in this study.ResultsThe measurement of blood pressure in vivo was similar in KO and WT mice. Pressure-induced myogenic tone, contractions to angiotensin-II and phenylephrine were similar in both groups. The inhibition of MMP2/9 ((2R)-2-[(4-biphenylylsulfonyl) amino]-3-phenylpropionic acid) significantly decreased myogenic tone in WT and had no effect in KO mice. Relaxation endothelium-dependent (flow-induced- dilation 41.3 ± 0.6 vs. 21 ± 1.6 at 10 μl/min in KO and WT mice, respectively, P < 0.05) and eNOS expression were increased in KO compared to WT mice. The inhibition of eNOS with L-NAME significantly decreased endothelium response to shear stress, which was more pronounced in KO mice resistance arteries (−26.83 ± 2.5 vs. −15.84 ± 2.3 at 10 μl/min in KO and WT, respectively, P < 0.05). However, the relaxation to exogenous nitric oxide-donor was similar in both groups.ConclusionOur study provides evidence of a selective effect of MMP-9 on endothelium function. Thus, MMP-9 gene deletion specifically increased resistance artery dilation endothelium-dependent and eNOS expression. Based on our results, MMP-9 could be a potential therapeutic target in cardiovascular disease associated with resistance arteries dysfunction.