Involvement of metalloproteinases 2/9 in epidermal growth factor receptor transactivation in pressure-induced myogenic tone in mouse mesenteric resistance arteries.
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).


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 micromol/L) or PD153035 (1 micromol/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.
Lucchesi
Pamela A
PA
Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, USA.
Sabri
Abdelkarim
A
Belmadani
Souad
S
Matrougui
Khalid
K
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D008638:Mesenteric Arteries / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction; D009129:Muscle Tonus / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D010766:Phosphorylation; D011189:Potassium Chloride / Q000494:pharmacology; D011312:Pressure; D015533:Transcriptional Activation; D014655:Vascular Resistance
C587884:Hbegf protein, mouse; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D061965:Matrix Metalloproteinase Inhibitors; D000804:Angiotensin II; D004815:Epidermal Growth Factor; D011189:Potassium Chloride; D066246:ErbB Receptors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9