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(Hypertension. 2007;50:212.)
© 2007 American Heart Association, Inc.

Sixth International Workshop on Structure and Function of the Vascular System

Role of Matrix Metalloproteinases in Early Hypertensive Vascular Remodeling

Martin Flamant; Sandrine Placier; Caroline Dubroca; Bruno Esposito; Izolina Lopes; Christos Chatziantoniou; Alain Tedgui; Jean-Claude Dussaule; Stéphanie Lehoux

From the Institut National de la Santé et de la Recherche Médicale (INSERM) U689 (C.D., B.E., I.L., A.T., S.L.), Centre de Recherche Cardiovasculaire Inserm Lariboisière, Paris, France; INSERM U702 (M.F., S.P., C.C., J-C.D.), Hôpital Tenon, Université Pierre et Marie Curie, Paris, France; and the Department of Physiology (J-C.D.), Hôpital St-Antoine, Paris, France.

Correspondence to Stéphanie Lehoux, Centre de Recherche Cardiovasculaire Inserm Lariboisière, INSERM U689, 41 Boulevard de la Chapelle, 75010 Paris, France. E-mail lehoux{at}larib.inserm.fr

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.

Key Words: angiotensin • metalloproteinases • remodeling • hypertension • collagen

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