on May 21, 2007
Published online before print May 21, 2007, doi: 10.1161/HYPERTENSIONAHA.107.089631
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Submitted on February 20, 2007
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. * To whom correspondence should be addressed. E-mail: lehoux{at}larib.inserm.fr.
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.
Revised on March 17, 2007
Role of Matrix Metalloproteinases in Early Hypertensive Vascular Remodeling
Martin Flamant;
Key words: angiotensin • metalloproteinases • remodeling • hypertension • collagen
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