Role of proteases in ischemia/reperfusion‐induced arteriolar endothelium‐dependent vasodilatory dysfunction.

Abstract

Intestinal ischemia and reperfusion (I/R) is associated with leukocyte rolling and adhesion in postcapillary venules, neutrophil infiltration and release of proteases in the interstitium, and endothelium‐dependent vasodilatory (EDD) dysfunction in arterioles. The aim of this study was to determine whether proteases were involved in the genesis of postischemic EDD. To address this issue, the responses of rat mesenteric arterioles (20‐40 µm diameter) to increasing doses of acetylcholine or nitroprusside were evaluated under control conditions (no ischemia) and after 20 min of ischemia and 60 min of reperfusion using intravital microscopy. In some groups, the mesentery was superfused with broad‐spectrum protease or selective matrix metalloproteinase (MMP) inhibitors during reperfusion. Intestinal I/R induced a significant deficit in endothelium‐dependent arteriolar responses to acetylcholine, but not nitroprusside. Postischemic EDD dysfunction was largely abolished by treatment with broad‐spectrum protease or selective MMP inhibitors. Comparable results were noted in isolated mesenteric arterioles (80‐140 µm) obtained from MMP‐9 knockout mice that had been subjected to mesenteric I/R. In summary, our data suggest that proteases, including MMP‐9, play an important role in the development of I/R‐induced arteriolar endothelium‐dependent vasodilator dysfunction. The work was supported by HL‐082816 from the NIH.