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 Ϫ/Ϫ mice were treated with angiotensin II (Ang II; 1 g/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 (PϽ0.05) in MMP-9 Ϫ/Ϫ mice (94Ϯ6 to 134Ϯ6 mm Hg; PϽ0.001) than in wt animals (93Ϯ4 to 114Ϯ6 mm Hg; PϽ0.01). In wt mice, Ang II treatment increased the carotid artery pressure-diameter relationship significantly, and maximal diameter reached 981Ϯ19 m (PϽ0.01 versus sham; 891Ϯ10 m). In contrast, in MMP-9 Ϫ/Ϫ mice, carotid artery compliance was actually reduced after Ang II (PϽ0.05), and maximal diameter only reached 878Ϯ13 m. 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 Ϫ/Ϫ counterparts (PϽ0.05). Inversely, staining for collagen IV was particularly enhanced in vessels from MMP-9 Ϫ/Ϫ 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. Key Words: angiotensin Ⅲ metalloproteinases Ⅲ remodeling Ⅲ hypertension Ⅲ collagen B lood pressure is a major determinant of vessel wall structure and composition. Any change in strain will generate counteracting radial and tangential forces that drive transformations in the vessel wall to accommodate the new pressure setting and restore basal levels of tensile stress. 1 It therefore follows that a key characteristic of hypertensive conductance arteries is increased wall thickness accompanied by enhanced rigidity. In hypertensive patients, this is manifest by elevated pulse wave velocity, an independent predictor of mortality in patients with end-stage renal failure, hypertension, and diabetes, as well as in older individuals. 2 Nevertheless, using an ex vivo model of carotid artery, we have shown recently that early vascular remodeling in the hypertensive context is actually associated with increased conductance vessel distensibility rather than rigidity. 3 In fact, results from our own laboratory 3 and others 4 -8 have shown that exposing arteries or vascular cells to stretch induces the release of matrix metalloproteinases (MMPs). This perplexing observation led us to hypothesize that increased compliance may be an early compensatory mechanism allowi...