Cardiovascular Research Advance Access originally published online on July 3, 2009
Cardiovascular Research 2009 84(3):368-377; doi:10.1093/cvr/cvp230
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Maintenance of adrenergic vascular tone by MMP transactivation of the EGFR requires PI3K and mitochondrial ATP synthesis
1 Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, 3-19 Medical Sciences Building, Edmonton, Alberta, Canada T6G 2H7
2 Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, British Columbia, Canada V6T 1Z3
* Corresponding authors. Tel: +1 780 492 9540; fax: +1 780 492 0886. E-mail address: cf2{at}ualberta.ca (C.F.-P.); Tel: +1 604 822 9373; fax: +1 604 822 8001. E-mail address: jmcneill{at}interchange.ubc.ca (J.H.M.)
Aims: G-protein-coupled receptors (GPCRs) modulate vascular tone, at least in part, via matrix metalloproteinase (MMP) transactivation of the epidermal growth factor receptor (EGFR). We previously have identified novel signalling pathways downstream of the EGFR suggestive of mitogen-activated protein kinase and mitochondrial redox control of vascular tone. In the present study, we examined whether MMP modulation of vascular tone involves phosphoinositide 3-kinase (PI3K) and mitochondrial ATP synthesis.
Methods and results: To determine whether PI3K is required for the maintenance of adrenergic vascular tone, we first constricted rat small mesenteric arteries with phenylephrine (PE) and then perfused with PI3K inhibitors, LY294002 and wortmannin, both of which produced a dose-dependent vasodilatation. Next, to investigate whether MMPs modulate PI3K activity, we cultured rat aortic vascular smooth muscle cells (VSMCs) and stimulated them with GPCR agonists such as PE and angiotensin 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 blunted the PI3K phosphorylation of Akt induced by PE. Further, in VSMCs, PI3K inhibitors reduced the PE-induced increase in ATP synthesis and glucose transporter-4 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.
Conclusion: These data suggest that the maintenance of adrenergic vascular tone by the MMP–EGFR pathway requires PI3K activation and ATP synthesis. Further, our data support 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.
KEYWORDS Matrix metalloproteinase; Epidermal growth factor receptor; Phosphoinositide 3-kinase; ATP; Adrenergic tone
Time for primary review: 29 days
Related Article
CiteULike 
Connotea 
Del.icio.us What's this?
Cardiovasc Res 2009 84: 339-340.
This article has been cited by other articles:
|
|
 |
|
  J. S. Isenberg and S. Shiva Vasoconstriction: tightening the noose through MMPs Cardiovasc Res, December 1, 2009; 84(3): 339 - 340. [Full Text] [PDF]
|
|