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Maintenance of adrenergic vascular tone by MMP transactivation of the EGFR requires PI3K and mitochondrial ATP

Prabhakara Reddy Nagareddy¹, Fung Lan Chow, Li Hao

¹Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Alberta, Canada T6G 2H7.

Cardiovascular Research

|July 7, 2009

Abstract

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.

Insights

Matrix metalloproteinases (MMPs) and epidermal growth factor receptor (EGFR) signaling require phosphoinositide 3-kinase (PI3K) and ATP synthesis to maintain vascular tone. This pathway may contribute to cardiovascular diseases like hypertension.

Area of Science:

Vascular Biology
Cell Signaling
Cardiovascular Physiology

Background:

G-protein-coupled receptors (GPCRs) influence vascular tone partly through matrix metalloproteinase (MMP) mediated transactivation of the epidermal growth factor receptor (EGFR).
Previous research identified signaling pathways downstream of EGFR involving mitogen-activated protein kinase and mitochondrial redox control in vascular tone.
The current study investigates the roles of phosphoinositide 3-kinase (PI3K) and mitochondrial ATP synthesis in MMP-mediated vascular tone modulation.

Purpose of the Study:

To determine if PI3K is essential for maintaining adrenergic vascular tone.
To investigate the mechanism by which MMPs modulate PI3K activity.
To explore the involvement of ATP synthesis in the MMP-EGFR pathway's effect on vascular tone.

Main Methods:

Rat mesenteric arteries constricted with phenylephrine (PE) were treated with PI3K inhibitors (LY294002, wortmannin) to assess vasodilatation.
Rat aortic vascular smooth muscle cells (VSMCs) were stimulated with GPCR agonists (PE, angiotensin II) and treated with MMP or EGFR inhibitors.
MMP and EGFR inhibition effects on PI3K phosphorylation of Akt, ATP synthesis, and glucose transporter-4 translocation were analyzed.

Main Results:

PI3K inhibitors induced dose-dependent vasodilatation in PE-constricted arteries.
Inhibition of MMPs or EGFR, or suppression of MMP-2/7 or EGFR expression, blunted PE-induced Akt phosphorylation in VSMCs.
PI3K inhibitors reduced PE-induced ATP synthesis and glucose transporter-4 translocation, an effect mirrored by MMP and EGFR inhibitors.

Conclusions:

The MMP-EGFR pathway's role in maintaining adrenergic vascular tone necessitates PI3K activation and ATP synthesis.
Elevated GPCR agonist levels can amplify the MMP-EGFR transactivation response.
This exaggerated response may contribute to increased vascular tone and cardiovascular diseases, including hypertension.

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