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on January 19, 2006

Arteriosclerosis, Thrombosis, and Vascular Biology. 2006
Published online before print January 19, 2006, doi: 10.1161/01.ATV.0000204344.90301.7c
A more recent version of this article appeared on April 1, 2006
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Submitted on October 17, 2005
Accepted on January 4, 2006

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

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

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

* To whom correspondence should be addressed. 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 {alpha}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 ({Delta}{psi}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.


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