Role of Matrix Metalloproteinases in Early Hypertensive Vascular Remodeling

Abstract

Hypertension is associated with vascular remodeling characterized by rearrangement of extracellular matrix proteins. To evaluate how matrix metalloproteinase (MMP)-9 contributes to the progression of hypertensive vascular disease in vivo, wild-type (wt) or MMP-9 −/− mice were treated with angiotensin II (Ang II; 1 μg/kg per minute, by minipump) plus a 5% NaCl diet during 10 days. Baseline blood pressure was equivalent in wt and knockout mice, but Ang II treatment increased systolic blood pressure to a greater extent ( P <0.05) in MMP-9 −/− mice (94±6 to 134±6 mm Hg; P <0.001) than in wt animals (93±4 to 114±6 mm Hg; P <0.01). In wt mice, Ang II treatment increased the carotid artery pressure-diameter relationship significantly, and maximal diameter reached 981±19 μm ( P <0.01 versus sham; 891±10 μm). In contrast, in MMP-9 −/− mice, carotid artery compliance was actually reduced after Ang II ( P <0.05), and maximal diameter only reached 878±13 μm. Ang II treatment induced MMP-2 and increased carotid media thickness equally in both phenotypes. However, MMP-9 induction and in situ gelatinase activity were only enhanced in Ang II-treated wt mice, and vessels from these mice also produced more collagen I breakdown products than their MMP-9 −/− counterparts ( P <0.05). Inversely, staining for collagen IV was particularly enhanced in vessels from MMP-9 −/− mice treated with Ang II. These results demonstrate the following: (1) the onset of Ang II-induced hypertension is accompanied by increased MMP-9 activity in conductance vessels; (2) absence of MMP-9 activity results in vessel stiffness and increased pulse pressure; and (3) MMP-9 activation is associated with a beneficial role early on in hypertension by preserving vessel compliance and alleviating blood pressure increase.