Rhythmicity of the Cerebral Myogenic Response and Vascular Cyp450 Expression.

摘要

Circadian rhythms in cardiovascular function are evident in daily variation of blood pressure, heart rate, vascular tone, thrombotic tendency, cerebral blood flow (CBF) and stroke incidence. These rhythms result from intricate coordination of rhythms in neural signaling, renal function, hormone levels, physiological state of arousal, behavior and environmental cues. Epoxyeicosatrienoic acids (EETs) are potent vasodilators known to be involved in regulation of cerebral blood flow and functional hyperemia. Cerebral neurons, glial cells and endothelial cells express cytochrome P450 (Cyp450) epoxygenases Cyp2c11 and Cyp4x1 that convert arachidonic acid (AA) to EETs. A role is played by EETs in a number of physiological mechanisms including angiogenesis, inhibition of platelet aggregation, cardiomyocyte protection during ischemia and, importantly, vasodilation and regulation of CBF. EETs are specifically involved in the functional hyperemic response, increasing nutritive blood flow to active neurons. Astrocytes are known to play a major role in coupling CBF to neural activity in that they synthesize and release EETs in response to membrane receptor stimulation by glutamate and adenosine released from active neurons. The release of EETs leads to activation of potassium channels in vascular smooth muscle cells (VSMC) and endothelial cells (EC) via multiple signaling pathways. This causes hyperpolarization of these cells and subsequent vasodilation and increased CBF.;Although CBF shows circadian variation, the expression patterns of Cyp450 epoxygenases over a 24-hour period have never been studied. In this dissertation we tested the hypothesis that cerebral vessels possess a functional clock mechanism, that Cyp4x1 and Cyp2c11 mRNA, protein and activity levels vary rhythmically in the rat brain and vasculature and that the myogenic response of cerebral vessels to increases in intraluminal pressure varies at different times of the circadian cycle.;Our data show for the first time that factors involved in the regulation of cerebral blood flow are expressed rhythmically and that the magnitude of the myogenic response varies diurnally. The peak response at 2am corresponds with the peak in cerebral blood flow indicating that the cerebral vasculature is most equipped to prevent surges in blood flow caused by increases in cerebral blood pressure at this time. It has also been shown that severity of damage caused by middle cerebral artery occlusion in rats is highest during the beginning of the activity period, which corresponds to the time of increased stroke incidence in humans. It is possible that the reduced capacity of the myogenic response during the early activity period observed in our study could contribute to this finding or to an increase in stroke incidence in rats at this time. In this case, it is possible that such a mechanism contributes to the increased morning stroke risk in humans.