doi: 10.1161/01.ATV.0000216428.90962.60
© 2006 American Heart Association, Inc.
Editorial |
Mitochondrial Redox Control of Matrix Metalloproteinase Signaling in Resistance Arteries
From the Kidney Research Centre, Ottawa Health Research Institute, University of Ottawa, Ontario, Canada.
Correspondence to Rhian M Touyz, MD, PhD, Canada Research Chair in Hypertension, Ottawa Health Research Institute, University of Ottawa, 451 Smyth Rd, Ottawa, ON, KIH 8M5. E-mail rtouyz{at}uottawa.ca
Key Words: reactive oxygen species • adrenergic receptors • transactivation • epidermal growth factor receptor • signal transduction • vascular tone
The importance of free radicals in the regulation of vascular tone was recognized in the late 1980s, when endothelium-derived relaxing factor was identified to be NO.1,2 More recently, it has become clear that other free radicals, such as superoxide (O2–), hydrogen peroxide (H2O2), and peroxynitrite (ONOO-) also modulate vascular reactivity.3,4 However, the exact role of reactive oxygen species (ROS) in the regulation of vascular contraction and relaxation remains elusive because vascular effects of free radicals are heterogeneous. Responses may differ depending on the species studied, the vascular bed under investigation, whether the endothelium is intact or denuded, and if studies are conducted in vitro or in vivo.5,6 Furthermore, vascular actions of ROS may be direct or indirect and responses vary depending on the source of the free radicals and their site of compartmentalization.
See page 819
Superoxide has been implicated both as a vasoconstrictor and as a vasodilator. In cerebral vessels, low concentrations of O2–, generated by NADPH oxidase or xanthine oxidase, induce vasodilation.7 These effects may be mediated directly by activating potassium channels or indirectly through interactions with NO.8 On the other hand, high concentrations of O2– are potent vasoconstrictors, probably induced by ROS-stimulated increase in intracellular free Ca2+ concentration ([Ca2+]i) or by increasing ONOO- production through interactions with NO.9,10 The inactivation of NO by superoxide results in the loss of the vasodilator effect of NO, which, together with the direct contractile actions of ONOO-, leads to vasoconstriction. Similar biphasic dose-dependent responses have been observed in aorta and resistance arteries11,12 and in cultured vascular smooth muscle cells.13
H2O2, which is lipid soluble and more stable than O2–, has been considered to be an endothelium-derived hyperpolarizing factor in some vascular beds.14,15 However, H2O2 may function as an endothelium-derived relaxing factor without producing hyperpolarization of underlying vascular muscle.16 Furthermore, in some vessels, H2O2 induces vasoconstriction and actually attenuates vasodilation.17–19 To further highlight the complex nature of ROS in vascular biology, it is now well accepted that ROS function not only as modulators of vascular tone but also as important mediators of vascular growth, inflammation, and fibrosis.20
Cellular mechanisms whereby ROS mediate their pleiotropic vascular effects are complex. Multiple signaling pathways stimulated by myriad vasoactive agents, such as angiotensin II (Ang II), endothelin-1, and aldosterone, and numerous redox-sensitive signaling molecules, including mitogen-activated protein kinases, tyrosine kinases, protein tyrosine phosphatases, matrix metalloproteinases (MMPs), and transcription factors, have been implicated.21–24
In the present issue of Arteriosclerosis, Thombosis, and Vascular Biology, Hao et al extend our understanding of how G-protein–coupled receptors (GPCRs) modulate redox-sensitive vascular tone, and these authors provide novel mechanistic insights as to how ROS can elicit both vasoconstriction and growth.25 In particular, using 
1-adrenergic receptors as a model of GPCR activators, they demonstrate in rat resistance arteries that MMP transactivation of the epidermal growth factor receptor (EGFR) modulates vascular tone and hypertrophy through mitochondrial-derived ROS (Figure). These findings suggest that MMP–ROS signaling may be a common pathway linking apparently unrelated events, which are critically involved in the pathobiology of vascular disease.
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A link between ROS and MMPs has been identified previously. ROS regulate MMP gene expression and activation of proenzymes. MMP-1, MMP-2, MMP-7, and MMP-9 are activated by ROS through interactions with thiol groups, in which the thiol residue is converted by ROS to sulfinic acid.26,27 Redox-sensitive MMP activation promotes collagen degradation and remodeling of extracellular matrix. MMPs are also critically involved in GPCR-mediated transactivation of growth factor receptors. EGFR transactivation requires MMP-dependent extracellular cleavage of pro–heparin-binding epidermal growth factor (HB-EGF), which liberates a soluble HB-EGF that activates EGFR.28 This "triple membrane-passing signaling" paradigm has been demonstrated for various GPCRs in different cellular backgrounds. In particular, triple membrane-passing signaling is pertinent to Ang II–mediated cell proliferation and growth in cardiac and vascular cells.29 Here we learn that -adrenoceptors also transactivate EGFR through MMPs, specifically MMP-7, and that this signaling pathway regulates redox-sensitive vascular contraction.25 The exact mechanisms involved in MMP mobilization and HB-EGF liberation are not yet established, but based on the findings of Hao et al,25 they do not seem to involve ROS because ROS scavenging did not influence MMP transactivation. On the other hand, ROS scavenging by L-N-acetylcysteine, superoxide dismutase, manganese (III) tetrakis (4-benzoic acid) porphrin (MnTBAP) (cell-permeable superoxide dismutase mimetic), and diphenylene iodinium inhibited adrenergic-stimulated vasoconstriction. Together, it seems that MMPs are upstream of ROS generation, at least in phenylephrine-induced contraction of rat small mesenteric arteries.
What is particularly interesting, and rather unexpected, in the study of Hao et al25 is the finding that agonist-stimulated vascular tone in the vasculature is independent of NAD(P)H oxidase because nonphagocytic NAD(P)H oxidase is generally considered the primary source of ROS in the vascular wall.30 NAD(P)H oxidase is a multisubunit enzyme that is activated by Ang II, aldosterone, growth factors, and stretch and is upregulated in conditions associated with oxidative stress and vascular damage.31,32 NADPH-driven generation of ROS promotes vascular growth, fibrosis, inflammation, and contraction.20,30–32 In the study of Hao,25 using various approaches to inhibit activation of NAD(P)H oxidase, including gp91ds-tat and apocynin, contractile responses to phenylephrine were unaffected, indicating that NAD(P)H oxidase does not contribute significantly to adrenergic-regulated vascular tone. Reasons why -adrenoceptors do not couple to NAD(P)H oxidase, unlike most GPCRs which do, are unclear.
If NAD(P)H oxidase is not responsible for adrenoceptor-mediated vascular ROS formation, what is? The authors provide convincing evidence that mitochondria are critically involved. Mitochondria play a complex multifactorial role in the cell. In addition to their primary function in ATP generation, the organelles sequester Ca2+, and both generate and detoxify ROS. All these functions are intimately interlinked through the central bioenergetic parameter of the proton electrochemical gradient across the inner mitochondrial membrane.33–35 In the study under consideration, pharmacological manipulation of mitochondrial electron transport by rotenone (complex I inhibitor), antimycin A (complex III inhibitor), cyanide (complex IV inhibitor), and oligomycin (complex V ATP synthase inhibitor), as well as the mitochondrial respiratory chain uncoupler carbonylcyanide m-chlorophenylhydrazone, all opposed adrenergic-mediated vasoconstriction, indicating the importance of mitochondria.25 To further support this, a mitochondria-selective ROS scavenger and fluorescent probe, Mito Tracker Red CM-H2XRos, was used to track mitochondrial ROS formation in agonist-stimulated vessels. It is intriguing that inhibition of complexes I, III, IV, and V blocked phenylephrine-induced vascular tone because it is primarily complex I and complex III that normally generate O2–.36,37 Also, because complex IV (cytochrome c oxidase) may act as a peroxidase, which scavenges free radicals,36,37 its role in adrenergic-associated oxidative stress is unclear.
There is growing evidence to confirm the findings of Hao et al25 that mitochondria are important sources of vascular ROS. Endothelin-1 promotes oxidative stress through mitochondrial ROS in human vascular smooth muscle cells38 and in deoxycorticosterone acetate–salt hypertension.39 Advanced glycation end-products increase mitochondrial-derived ROS in cultured vascular smooth muscle cells.40 Bailey et al reported that ROS from smooth muscle mitochondria initiate cold-induced constriction of mouse cutaneous arteries by selectively increasing the activity of smooth muscle 2-adrenoceptors.41
There are some limitations that should be kept in mind when interpreting the findings of the study by Hao et al.25 First, numerous pharmacological agents were used in whole vessels. In such preparations in which cell type is heterogeneous and in which different species of free radicals localize in different vascular and subcellular compartments, the specificity of pharmacological manipulators used remains questionable. Second, for mitochondrial-derived ROS to be detected in the arterial releasate, as demonstrated in response to phenylephrine, levels of mitochondrial ROS must be very high or mitochondrial antioxidant defense systems must be overwhelmed, indicating possible mitochondrial damage. Third, although the authors demonstrated an association between -adrenoceptors, MMP-7, EGFR, and mitochondrial ROS-generating systems, the exact molecular mechanisms linking these components is unknown. Furthermore, it remains to be determined how mitochondrial ROS actually influence the contractile machinery in mesenteric arteries.
Nevertheless, the study under consideration has important strengths that need to be highlighted. First, the authors identified that in response to phenylephrine, ROS is generated through NAD(P)H oxidase–independent, mitochondrial-dependent enzymes. Others also recently demonstrated the importance of redox-mediated contraction independently of NADPH oxidase.42 Second, it is clearly demonstrated, using small interfering RNA and pharmacological tools, that MMP-7–EGFR transactivation is upstream and not downstream of ROS, as generally accepted. Finally, the study provides new insights into common signaling pathways, which may influence both constriction and growth, important processes in vascular pathology.
In recent years, our perception of GPCR modulation of vascular tone by ROS has expanded considerably. We are beginning to appreciate that in addition to regulating vascular growth and inflammation, ROS can influence contraction and dilation and that responses are highly variable depending on the agonist, the vascular bed, and the species generated. However, at present, it is still unclear exactly what the regulatory functions of ROS are with respect to vascular contraction/dilation in physiological conditions, and it is even more confusing and puzzling when attempting to unravel the role of these complex processes in pathological situations. Clearly, future research must focus on the significance of redox-sensitive vascular tone and on the molecular mechanisms whereby ROS regulate vascular contraction/dilation. Thus, the study of Hao et al25 is important because it describes a novel signaling pathway involving MMPs, EGFR, and mitochondria, whereby GPCRs, specifically 1-adrenergic receptors, regulate vascular contraction through ROS. Such findings, together with those of other findings,43,44 contribute to the further understanding of how vasoactive agonists that induce MMP transactivation of the EGFR modulate redox-sensitive vascular tone.
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Related Article:
1-Adrenergic Receptors in Small Rat Mesenteric Arteries Depend on Mitochondrial Reactive Oxygen Species
Arterioscler. Thromb. Vasc. Biol. 2006 26: 819-825.
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