Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 3, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp230
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Maintenance of adrenergic vascular tone by MMP-transactivation of the EGFR requires PI3K and mitochondrial ATP synthesis
1 Dept of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
2 Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada
* Corresponding Authors: Dr. Carlos Fernandez-Patron, Associate Professor, Department of Biochemistry, University of Alberta, 3-19 Medical Sciences Building, Edmonton, Alberta T6G 2H7, Canada. Tel: 780-492-9540; Fax: 780- 492-0886; E-mail: cf2{at}ualberta.ca, Dr. John H McNeill, Professor, Faculty of Pharmaceutical Sciences, 2146 East Mall, The University of British Columbia, Vancouver, BC, Canada, V6T 1Z3. Phone: 604-822-9373; Fax: 604-822-8001; Email: jmcneill{at}interchange.ubc.ca
Aims: G-protein coupled receptors (GPCR) modulate vascular tone, at least in part, via matrix metalloproteinase (MMP)-transactivation of the epidermal growth factor receptor (EGFR). We previously have identified novel-signaling pathways downstream of the EGFR suggestive of mitogen-activated protein kinase (MAPK) and mitochondrial redox control of vascular tone. In the present study, we examined whether MMP modulation of vascular tone involves phosphoinositide 3-kinase (PI3-kinase) and mitochondrial ATP synthesis.
Methods and Results: To determine whether PI3-Kinase is required for the maintenance of adrenergic vascular tone, we first constricted rat small mesenteric arteries with phenylephrine (PE) and then perfused with PI3-kinase inhibitors, LY294002 and wortmannin, both of which produced a dose dependent vasodilatation. Next, to investigate whether MMPs modulate PI3-kinase activity, we cultured rat aortic vascular smooth muscle (VSM) cells and stimulated them with GPCR agonists such as PE and angiotensin II (AT II). Inhibition of MMPs (by GM6001) or EGFR (by AG1478) or suppressing the expression of MMP-2 or MMP-7 or the EGFR by small interfering RNA (siRNA) blunted the PI3-kinase phosphorylation of Akt induced by PE. Further, in VSM cells, PI3-kinase inhibitors reduced the PE induced increase in ATP synthesis and glucose transporter-4 (GLUT4) translocation, an effect that was also observed with MMP and the EGFR inhibitors. Further, the PE-induced increase in ATP synthesis activated MMP-7 by mechanisms involving purinergic (P2X) receptors and calcium.
Conclusions: These data suggest that maintenance of adrenergic vascular tone by the MMP-EGFR pathway requires PI3-kinase activation and ATP synthesis. Further, our data supports the view that elevated levels of GPCR agonists exaggerate the MMP transactivation of EGFR response and contribute to enhanced vascular tone and development of cardiovascular disease such as hypertension.
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Cardiovasc Res 2009 84: 339-340.
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  J. S. Isenberg and S. Shiva Vasoconstriction: tightening the noose through MMPs Cardiovasc Res, December 1, 2009; 84(3): 339 - 340. [Full Text] [PDF]
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