Published Online
on November 22, 2004

A more recent version of this article appeared on December 7, 2004

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Submitted on May 11, 2004
Revised on August 4, 2004
Accepted on September 8, 2004

Involvement of Metalloproteinases 2/9 in Epidermal Growth Factor Receptor Transactivation in Pressure-Induced Myogenic Tone in Mouse Mesenteric Resistance Arteries

Pamela A. Lucchesi PhD, Abdelkarim Sabri PhD, Souad Belmadani PhD, and Khalid Matrougui PhD^*

From the Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans (P.A.L., K.M.), and the Department of Physiology and Biophysics, University of Alabama at Birmingham (A.S., S.B.).

^* To whom correspondence should be addressed. E-mail: kmatro{at}lsuhsc.edu.

Background--Epidermal growth factor receptor (EGFR) transactivation is a mediator of angiotensin II (Ang II) signaling in cultured vascular smooth muscle cells isolated from large arteries. The present study used mouse mesenteric resistance arteries (MRAs) to investigate the role of EGFR transactivation under pressure-induced myogenic tone (MT).

Methods and Results--Isolated MRAs were mounted in an arteriograph and stimulated by 25 to 125 mm Hg or with Ang II and KCl. Stepwise increases in pressure resulted in MT development associated with increased EGFR phosphorylation and release of heparin-binding EGF (HB-EGF), a membrane-bound growth factor that is shed on cleavage by metalloproteinases. EGF (50 ng/mL) potentiated MT (59±1% to 51±0.6% of passive diameter at 75 mm Hg). Pretreatment with the EGFR inhibitors AG1478 (5 µmol/L) or PD153035 (1 µmol/L) significantly decreased MT. However, EGFR inhibitors had no effect on Ang II- and KCl-induced contraction. MT was potentiated by HB-EGF, 50 ng/mL, which is bound to the cell membrane and released on cleavage by metalloproteinases. Neutralizing HB-EGF antibodies or heparin treatment to sequester HB-EGF resulted in significant inhibition of pressure-induced MT. MT increased matrix metalloproteinase (MMP) 2 and MMP-9 gelatinase activity assessed by zymography, and specific MMP 2/9 inhibitors significantly decreased MT.

Conclusions--These novel findings suggest that the mechanism of pressure-induced MT involves metalloproteinases 2/9 activation with subsequent HB-EGF release and EGFR transactivation.

Key words: microcirculation • metalloproteinases • growth substances • angiotensin • pressure

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