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Hypertension is associated with vascular remodeling characterized by rearrangement of extracellular matrix proteins. We recently showed that in isolated vessels, high intraluminal pressure activates the matrix metalloproteinase MMP-9, resulting in early enhanced distensibility. To evaluate how MMPs contribute to the progression of hypertensive vascular disease in vivo, mice deficient in MMP-9 or control (wt) littermates were treated with angiotensin II (1 µg/kg/day minipump) plus 5% NaCl diet (AngII) during 10 days. Baseline blood pressure was equivalent in wt and knockout mice, but AngII treatment increased blood pressure to a greater extent (P<0.01) in MMP-9-/- mice (94±6 to 137±2 mmHg; P<0.01) than in wt animals (88±4 to 114±8 mmHg; P<0.05). To assess underlying mechanisms, vessels were removed at day 10 and processed. Compliance of mesenteric arterioles was not altered by AngII in any mice. However, in wt mice, AngII treatment increased the carotid artery pressure-diameter relationship significantly, and maximal diameter reached 981±19µm (P<0.01 vs sham, 891±10µm). In contrast, in MMP-9-/- mice carotid artery compliance was actually reduced after AngII (P<0.05), and maximal diameter only reached 878±13µm. AngII treatment induced MMP-2 and increased media thickness in both phenotypes. However, MMP-9 induction and in situ gelatinase activity were only enhanced in AngII-treated wt mice, and vessels from these mice also produced more collagen I breakdown products (CITP) than their wt counterparts (P<0.05). On the other hand, staining for collagen IV was particularly enhanced in vessels from MMP-9-/- mice treated with AngII. These results suggest that 1) increased distensibility is a hallmark of early hypertensive remodeling, 2) in the short term, accrued distensibility correlates with a more moderate increase in blood pressure levels in a pro-hypertensive hormonal environment, and 3) MMP-9 plays a key role in this protective remodeling response.
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J. Vasc. Biol. 42, Sup:2 (2005) p75