Much of what is known about reactive oxygen species (ROS) and the control of blood flow is phenomenological with less understood regarding cellular and molecular mechanisms of action. The purpose of this proposal is to define some of the cellular and ionic mechanisms through which O2.- and H2O2 modulate myogenic autoregulation of cerebral blood flow (CBF). H2O2 reduces the degree of autoregulation (autoregulatory index, AI) in response to increasing transmural pressure in both isolated pressurized cerebral arterioles as well as reducing AI upon increasing mean arterial pressure in vivo. The action of H2O2 to reduce smooth muscle activation appears to involve modulation of the signaling cascade initiated via phospholipase C gamma-1, and related phosphoinositol 3 kinase and phosphatases. Part of the signaling cascade by H2O2 involves activation of Ca2+ activated K+ channels regulated by PKC. These data demonstrate that the cellular/ionic mechanisms of O2.- and H2O2 on cerebral arterial muscle and autoregulation is via cleavage of PIP2 and resultant formation of IP3 and DAG. We have found that adenosine, released from metabolically active neurons and astrocytes initiates formation of ROS in cerebral arterial muscle cells. Such data links neuronal metabolic activity modulating pressure-dependent myogenic tone - thereby, defining the actions of O2.- and H2O2 on autoregulation of CBF under resting conditions and in response to increased neural metabolic activity. We hope to develop a mathematical algorithm to stimulate local blood flow in the brain. While these are future plans they are possible in that the model will include measurable parameters i.e. passive, shear-dependent, myogenic and metabolic responses and their mechanisms. Previous models have been developed and have only explored autoregulation and have not been able to distinguish the relative concentrations of the aforementioned parameters. We hope Dr. Daniel;Beard has agreed to act as our consultant and use data obtained in this project to guide future basic and clinical investigations into models of cerebral blood flow regulation.
Blood flow to the brain is regulated differently than that of other organs. The brain is in a rigid closed space, therefore, blood flow must be autoregulated so that a change in arterial pressure does not cause a change in pressure in the brain. This autoregulation is controlled by molecules which sense the need for blood as neurons need more oxygen. In addition, the cerebral vessels exhibit their own control termed myogenic tone. This myogenic tone is a major topic of this application. We will determine how myogenic tone occurs and how it is regulated under normal and abnormal conditions to make sure there is enough blood flow to neurons so the brain can work properly.
|Zhang, Yue; Hong, Gina; Lee, Kin Sing Stephen et al. (2017) Inhibition of soluble epoxide hydrolase augments astrocyte release of vascular endothelial growth factor and neuronal recovery after oxygen-glucose deprivation. J Neurochem 140:814-825|
|Pabbidi, Mallikarjuna R; Roman, Richard J (2017) Elevated K+ channel activity opposes vasoconstrictor response to serotonin in cerebral arteries of the Fawn Hooded Hypertensive rat. Physiol Genomics 49:27-36|
|Zhang, Hui; Falck, John R; Roman, Richard J et al. (2017) Upregulation of 20-HETE Synthetic Cytochrome P450 Isoforms by Oxygen-Glucose Deprivation in Cortical Neurons. Cell Mol Neurobiol 37:1279-1286|
|Gebremedhin, Debebe; Zhang, David X; Carver, Koryn A et al. (2016) Expression of CYP 4A ?-hydroxylase and formation of 20-hydroxyeicosatetreanoic acid (20-HETE) in cultured rat brain astrocytes. Prostaglandins Other Lipid Mediat 124:16-26|
|Liu, Xiaoguang; Gebremedhin, Debebe; Harder, David R et al. (2015) Contribution of epoxyeicosatrienoic acids to the cerebral blood flow response to hypoxemia. J Appl Physiol (1985) 119:1202-9|
|Pabbidi, Mallikarjuna R; Mazur, Olga; Fan, Fan et al. (2014) Enhanced large conductance K+ channel activity contributes to the impaired myogenic response in the cerebral vasculature of Fawn Hooded Hypertensive rats. Am J Physiol Heart Circ Physiol 306:H989-H1000|
|Gebremedhin, Debebe; Gopalakrishnan, Sandeep; Harder, David R (2014) Endogenous events modulating myogenic regulation of cerebrovascular function. Curr Vasc Pharmacol 12:810-7|
|Carver, Koryn A; Lourim, David; Tryba, Andrew K et al. (2014) Rhythmic expression of cytochrome P450 epoxygenases CYP4x1 and CYP2c11 in the rat brain and vasculature. Am J Physiol Cell Physiol 307:C989-98|
|Sarkar, Pallabi; Zaja, Ivan; Bienengraeber, Martin et al. (2014) Epoxyeicosatrienoic acids pretreatment improves amyloid ?-induced mitochondrial dysfunction in cultured rat hippocampal astrocytes. Am J Physiol Heart Circ Physiol 306:H475-84|
|Wickramasekera, Nadi T; Gebremedhin, Debebe; Carver, Koryn A et al. (2013) Role of dual-specificity protein phosphatase-5 in modulating the myogenic response in rat cerebral arteries. J Appl Physiol 114:252-61|
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