Role of matrix metalloproteinases in early hypertensive vascular remodeling.
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 microg/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 microm (P<0.01 versus sham; 891+/-10 microm). 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 microm. 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.
Flamant
Martin
M
Institut National de la Santé et de la Recherche Médicale (INSERM) U689, Centre de Recherche Cardiovasculaire Inserm Lariboisière, Paris, France.
Placier
Sandrine
S
Dubroca
Caroline
C
Esposito
Bruno
B
Lopes
Izolina
I
Chatziantoniou
Christos
C
Tedgui
Alain
A
Dussaule
Jean-Claude
JC
Lehoux
Stéphanie
S
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000503:physiopathology*; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D003187:Compliance; D004789:Enzyme Activation; D006973:Hypertension / Q000201:enzymology / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017540:Tunica Media / Q000187:drug effects / Q000473:pathology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D020780:Matrix Metalloproteinase 9