Roles of Oxidant Signaling Mechanisms in Microvascular Function

The fundamental roles ROS and RNS play in cellular signaling processes provide these reactive species with a wealth of roles in the control of microvascular function. A combination of the local balance between the activities of NO- and O2--generating systems and ROS- and RNS-scavenging systems, localized redox perturbations caused by these species, the function of other non-ROS signaling systems, and energy metabolism-related balances originating from the delivery of O2 and the work-related metabolic needs of the tissue are likely to all function together as an integrated interactive system that controls the expression and importance of each individual cellular signaling mechanism involving ROS and RNS in the microcirculation. Signaling systems sensitive to regulation by low levels of ROS seem to have important coordinated roles in the acute vasoactive and more chronic adaptive physiological responses to changes in PO2, flow, and pressure. Aging and multiple vascular disease processes including hypertension, atherosclerosis, diabetes, heart failure, and ischemia activate increased ROS and RNS production in the vessel wall through multiple mechanisms, resulting in impaired endothelium-derived NO mediated relaxation and a suppression of the antithrombotic and anti-inflammatory actions of NO, increased expression of adhesion proteins, and endothelial cell permeability. Thus, at elevated levels of

ROS and RNS, signaling mechanisms controlled by these species appear to actively participate in promoting the progression of microvascular disease processes.


Oxidant signaling mechanisms: Processes involved in controlling the generation of reactive O2 species and their interactions with specific systems that regulate cellular function.

Reactive O2 species: Low-molecular-weight oxygen-containing biological molecules resulting from electrons being transferred to O2, which are generally quite unstable and reactive with other specific cellular molecules or protein functional groups.

Redox signaling: Processes involved in the control of low-molecular-weight biological molecules and protein functional groups that exist in various oxidized and reduced forms having a role in regulating specific systems that control cellular function.


Cai, H., and Harrison, D. G. (2000). Endothelial dysfunction in cardiovascular diseases: The role of oxidant stress. Circ. Res. 87, 840-844. Dröge, W. (2002). Free radicals in the physiological control of cell function. Physiol. Rev. 82, 47-95. Griendling, K. K., Sorescu, D., Lassegue, B., and Ushio-Fukai, M. (2000). Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiol-ogy. Arterioscler. Thromb. Vasc. Biol. 20, 2175-2183. Griendling, K. K., Sorescu, D., and Ushio-Fukai, M. (2000). NAD(P)H oxidase: Role in cardiovascular biology and disease. Circ. Res. 86, 494-501.

Lassegue, B., and Clempus, R. E. (2003). Vascular NAD(P)H oxidases: Specific features, expression, and regulation. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 285, 277-297. Thannickal, V. J., and Fanburg, B. L. (2000). Reactive oxygen species in cell signaling. Am. J. Physiol. Lung Cell. Mol. Physiol. 279, 1005-1028. This is a broad review on how reactive oxygen species can function in cellular signaling processes. Wolin, M. S. (2000). Interactions of oxidants with vascular signaling systems. Arteroscler. Thromb. Vasc. Biol. 20, 1430-1442. Wolin, M. S., Burke-Wolin, T. M., and Mohazzab-H., K. M. (1999). Roles for NAD(P)H oxidases and reactive oxygen species in vascular oxygen sensing mechanisms. Respir. Physiol. 115, 229-238. The focus of this review is how NAD(P)H oxidase can function in the role of a vascular oxygen sensor.

Wolin, M. S., Gupte, S. A., and Oeckler, R. A. (2002). Superoxide in the vascular system. J. Vasc. Res. 39, 191-207. This is an in depth review on the control of vascular contractile function by superoxide anion and its derived species.

Capsule Biography

The doctoral work of Michael S. Wolin was focused on characterizing the catalytic mechanism of the adenylate cyclase, and he received his Ph.D. in chemistry in 1982 from Yale University. He then joined the laboratory of Louis J. Ignarro in the Department of Pharmacology at Tulane University, and his postdoctoral studies involved elucidating how NO, free radicals, and heme modification regulate soluble guanylate cyclase. He then joined the faculty of the Department of Physiology at New York Medical College in 1983, where he is currently Professor of Physiology, with research interests that focus on how reactive species derived from O2 and NO participate in signaling mechanisms regulating vascular and microvascular function, with a focus on the soluble guanylate cyclase system, O2 sensing mechanisms, and endothelial-vascular regulation.

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