Mechanisms Regulating Cerebral Blood Flow

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DESCRIPTION (provided by applicant): The goal of this PPG is to define the mechanisms through which cytochrome P450 (CYP) metabolites of fatty acids control nutritive cerebral blood flow (CBF) under normal and pathologic conditions (inflammation, subarachnoid hemorrhage (SAH) and reactive hyperemia). The grant contains 3 interdependent scientific projects and 2 cores (administrative and biochemical/molecular) that support and facilitate the research in the program. When this program was first funded 4 years ago, the concept that CYP metabolites of arachidonic acid (AA), notably epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), played any role in the regulation of cerebral vascular tone by regulating ion channel activity was novel and was met with considerable skepticism. However, largely because of the progress made in this program and the large number of publications generated, most investigators now believe that CYP metabolites of AA play an important role in the autoregulation of cerebral vascular tone, functional hyperemia and angiogenesis in the brain by regulating K+ channel activity in the cerebral arteries. This renewal application builds upon the outstanding progress and accomplishments made over the last 4 years. Project 1 will examine the properties, substrate specificity and role of CYP4F and 4X isoforms that Dr. Harder and his group recently cloned and expressed from the brain of rats on the metabolism of AA and other substmtes (DHA and LTB4). They will then define the effects of the metabolites formed on cerebral vascular tone and cerebral inflammation. Project 2 headed by Dr. Roman will explore the role of 20-HETE in the regulation of cerebral vascular tone following SAH in the rat. Project 3 will explore various aspects of a unique hypothesis for reactive hyperremia in the brain. Drs. Koehler and Gebremedhin will determine if glutamate released by neurons stimulates receptors on astrocytes to open novel Kc, channels and increase capacitive Ca 2+ entry in these cells. They propose that the elevation in Ca 2+ concentration stimulates the synthesis and/or release of EETs by astrocytes and dilates the adjacent cerebral vessels by opening Kca channels in these cells. Each of the projects will utilize the biochemical/molecular core for LC/MS measurements of EETs, 20-HETE and structural identification of other CYP metabolites of fatty acids. In addition, the work on all three projects will be supported through a consortium agreement with Dr. Falck of the University of Texas Southwestern Medical Center who will synthesize and provide inhibitors, agonists and antagonists. This program reflects a long-standing tradition of sharing technology and ideas between the program investigators and will greatly increase our understanding of the role of CYP fatty acids in the control of cerebral blood flow both in health and following SAH.