Oxidant and redox signaling in vascular oxygen sensing mechanisms: basic concepts, current controversies, and potential importance of cytosolic NADPH

Abstract

Wolin, Michael S., Mansoor Ahmad, and Sachin A. Gupte. Oxidant and redox signaling in vascular oxygen sensing mechanisms: basic concepts, current controversies, and potential importance of cytosolic NADPH. Am J Physiol Lung Cell Mol Physiol 289: L159 -L173, 2005; doi:10.1152/ajplung.00060.2005.-Vascular smooth muscle (VSM) derived from pulmonary arteries generally contract to hypoxia, whereas VSM from systemic arteries usually relax, indicating the presence of basic oxygen-sensing mechanisms in VSM that are adapted to the environment from which they are derived. This review considers how fundamental processes associated with the generation of reactive oxygen species (ROS) by oxidase enzymes, the metabolic control of cytosolic NADH, NADPH and glutathione redox systems, and mitochondrial function interact with signaling systems regulating vascular force in a manner that is potentially adapted to be involved in PO 2 sensing. Evidence for opposing hypotheses of hypoxia, either decreasing or increasing mitochondrial ROS, is considered together with the PO2 dependence of ROS production by Nox oxidases as sensors potentially contributing to hypoxic pulmonary vasoconstriction. Processes through which ROS and NAD(P)H redox changes potentially control interactive signaling systems, including soluble guanylate cyclase, potassium channels, and intracellular calcium are discussed together with the data supporting their regulation by redox in responses to hypoxia. Evidence for hypothesized potential differences between systemic and pulmonary arteries originating from properties of mitochondrial ROS generation and the redox sensitivity of potassium channels is compared with a new hypothesis in which differences in the control of cytosolic NADPH redox by the pentose phosphate pathway results in increased NADPH and Nox oxidase-derived ROS in pulmonary arteries, whereas lower levels of glucose-6-phosphate dehydrogenase in coronary arteries may permit hypoxia to activate a vasodilator mechanism controlled by oxidation of cytosolic NADPH. hydrogen peroxide; hypoxia; Nox oxidase; mitochondria; pentose phosphate pathway PROCESSES THAT POTENTIALLY FUNCTION AS OXYGEN SENSORSThe direct binding of O 2 to a protein such as the hemecontaining soluble guanylate cyclase (sGC) (31, 89) that is directly linked to the control of cellular function would be an ideal way of sensing changes in PO 2 . However, a protein of this type has not yet been identified in vascular tissue. The substrate requirement for enzymes that metabolize oxygen is usually one of the most fundamental mechanisms through which PO 2 is sensed at the cellular level. Although the oxygen requirement for mitochondrial energy metabolism needed for the generation of force is the most basic mechanism of tissue oxygen sensing, there are only a few instances where this process appears to be the primary mechanism present in blood vessels controlling their response to acute changes in force elicited by hypoxia (95,101). Thus other aspects of the activities of oxygen metabolizing enzym...

Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange

“…6). The signaling mechanisms underlying the acute, prolonged and chronic effects of alveolar hypoxia on the pulmonary vasculature are still largely unknown (16)(17)(18)(19)(20). At present it is not clear whether the very acute hypoxic vasoconstrictor response (occurring within seconds), the prolonged response (occurring within hours), and the initiation of the structural vascular remodeling process in chronic hypoxia are regulated by identical or different mechanisms (3).…”

Regulation of cardiotrophin-1 expression in mouse embryonic stem cells by HIF-1α and intracellular reactive oxygen species

“…*P<0.05, significantly different from levels in the untreated control; # P<0.05, significantly different to levels before addition of 2-ME. respiratory chain or NADPH oxidase activity (Wolin et al, 2005). Elevated ROS are known to occur in cardiac infarction and are suspected to cause ischemia-reperfusion injury (Berg et al, 2005).…”

Redox Regulation in the Extracellular Environment

“…In vascular cells, other enzymatic sources of ROS include cytochrome P450 isoenzymes, lipoxygenase, cyclooxygenase, heme oxygenase, and glucose oxidase. 1,3,[5][6][7] Most reviews to date have focused on the role of intracellular antioxidants that eliminate ROS from the intracellular environment. There are, however, several extracellular antioxidants that also play an equally important role in limiting ROS accumulation in the extracellular environment.…”