Published Online
on February 16, 2004

A more recent version of this article appeared on March 2, 2004

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Submitted on September 3, 2003
Revised on October 16, 2003
Accepted on October 23, 2003

Pressure-Induced Matrix Metalloproteinase-9 Contributes to Early Hypertensive Remodeling

Stéphanie Lehoux PhD^*, Catherine A. Lemarié MSc, Bruno Esposito; , H. Roger Lijnen PhD, and Alain Tedgui PhD

From INSERM U541, Hôpital Lariboisière, Paris, France, and the Center for Molecular and Vascular Biology, University of Leuven, Belgium (H.R.L.).

^* To whom correspondence should be addressed. E-mail: lehoux{at}larib.inserm.fr.

Background--High blood pressure causes a change in vascular wall structure involving altered extracellular matrix composition, but how this process occurs is not fully understood.

Methods and Results--Using mouse carotid arteries maintained in organ culture for 3 days, we detected increased gelatin zymographic activity of matrix metalloproteinase (MMP)-2 (168±13%, P<0.05) in vessels kept at low intraluminal pressure (10 mm Hg) compared with vessels at 80 mm Hg (100%), whereas in vessels maintained at high pressure (150 mm Hg), both MMP-2 and MMP-9 activity was induced (182±32%, P<0.05, and 194±21%, P<0.01, respectively). MMPs were detected in endothelial and smooth muscle cells by immunohistochemistry and in situ gelatin zymography. In vessels at 150 mm Hg, MMP activation was associated with a shift in the pressure-diameter curve toward greater distensibility (P<0.01) compared with vessels at 80 mm Hg. However, distensibility was not altered in vessels at 10 mm Hg, in which only activated MMP-2 was detected. The role of MMPs in high pressure-induced vessel distensibility was confirmed by use of the MMP inhibitor FN-439, which prevented the shift in the pressure-diameter relationship. Furthermore, in carotid arteries from MMP-9-deficient mice, the pressure-dependent increase in MMP-2 and in situ gelatinolytic activity were maintained, but the upward shift in the pressure-diameter curve was abolished.

Conclusions--MMP-9 seems to play a key role in the early stages of hypertensive vascular remodeling.

Key words: arteries • hypertension • metalloproteinases • remodeling • signal transduction

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