Document Detail

Involvement of metalloproteinases 2/9 in epidermal growth factor receptor transactivation in pressure-induced myogenic tone in mouse mesenteric resistance arteries.
MedLine Citation:
PMID:  15557365     Owner:  NLM     Status:  MEDLINE    
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 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.
Pamela A Lucchesi; Abdelkarim Sabri; Souad Belmadani; Khalid Matrougui
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2004-11-22
Journal Detail:
Title:  Circulation     Volume:  110     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2004 Dec 
Date Detail:
Created Date:  2004-12-07     Completed Date:  2005-06-03     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3587-93     Citation Subset:  AIM; IM    
Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, USA.
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MeSH Terms
Angiotensin II / pharmacology
Epidermal Growth Factor / metabolism
Intercellular Signaling Peptides and Proteins
Matrix Metalloproteinase 2 / antagonists & inhibitors,  metabolism*
Matrix Metalloproteinase 9 / antagonists & inhibitors,  metabolism*
Mesenteric Arteries / physiology*
Mice, Inbred C57BL
Muscle Contraction
Muscle Tonus / physiology*
Muscle, Smooth, Vascular / physiology*
Potassium Chloride / pharmacology
Receptor, Epidermal Growth Factor / antagonists & inhibitors,  metabolism*
Transcriptional Activation
Vascular Resistance*
Grant Support
Reg. No./Substance:
0/Intercellular Signaling Peptides and Proteins; 11128-99-7/Angiotensin II; 149176-25-0/heparin-binding EGF-like growth factor; 62229-50-9/Epidermal Growth Factor; 7447-40-7/Potassium Chloride; EC, Epidermal Growth Factor; EC Metalloproteinase 2; EC Metalloproteinase 9

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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