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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:819.)
© 2006 American Heart Association, Inc.

Vascular Biology

Vascular Responses to ₁-Adrenergic Receptors in Small Rat Mesenteric Arteries Depend on Mitochondrial Reactive Oxygen Species

Li Hao; Tamiko Nishimura; Hua Wo; Carlos Fernandez-Patron

From the Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.

Correspondence to Dr Carlos Fernandez-Patron, Assistant Professor, Department of Biochemistry, 3-19 Medical Sciences Building, University of Alberta, Edmonton, Alberta T6G 2H7, Canada. E-mail carlos.fernandez-patron{at}ualberta.ca

Background— Agonists of G-protein–coupled receptors (eg, adrenoceptors and angiotensin receptors) signal, at least in part, through matrix metalloproteinases (such as matrix metalloproteinase [MMP]-7) that transactivate the epidermal growth factor receptor (EGFR). Focusing on adrenoceptors, we examined whether the MMP-dependent signaling pathway depends on reactive oxygen species (ROS).

Methods and Results— In isolated rat mesenteric arteries, selective stimulation of ₁-adrenoceptors with phenylephrine induced MMP transactivation of the EGFR, mitochondrial ROS production (detected by MitoTrackerRed-CM-H₂XRos-fluorescence and dihydroethidium-fluorescence and high-performance liquid chromatography [HPLC]/MS assay) and vasoconstriction. Inhibition of the synthesis of either MMP-7 or EGFR with anti-sense or siRNA oligonucleotides, respectively, decreased mitochondrial ROS production in response to phenylephrine. Targeted mitochondrial ROS scavenging with MitoTrackerRed-CM-H₂XRos inhibited adrenergic vasoconstriction. Adrenoceptor-induced ROS increased mitochondrial membrane potential (m), which was prevented by blockers of MMPs (GM6001, doxycycline), EGFR (AG1478), or complex I, all of which also prevented ROS production as well as vasoconstriction.

Conclusions— Production of mitochondrial ROS is a new event in the pathway by which vasoactive agonists that induce MMP transactivation of the EGFR modulate vascular tone. Moreover, our findings suggest a connection between agonist-induced activity of MMPs, the promotion of oxidative stress, enhanced vascular tone, and hypertrophy, which are all implicated in the development and progression of vascular disease.

Agonists of G-protein–coupled receptors (eg, adrenoceptors and angiotensin receptors) signal, at least in part, through matrix metalloproteinases (such as matrix metalloproteinase [MMP]-7) that transactivate the epidermal growth factor receptor (EGFR). Focusing on adrenoceptors, we examined whether the MMP-dependent signaling pathway depends on reactive oxygen species (ROS). Production of mitochondrial ROS is a new event in the pathway by which vasoactive agonists that induce MMP transactivation of the EGFR modulate vascular tone. Moreover, our findings suggest a connection between agonist-induced activity of MMPs, the promotion of oxidative stress, enhanced vascular tone, and hypertrophy, which are all implicated in the development and progression of vascular disease.

Key Words: adrenergic • G-protein coupled receptor (GPCR) • matrix metalloproteinase (MMP) • growth factor receptor • signalling • mitochondria • reactive oxygen species (ROS) • membrane potential • vascular

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