Obstructive sleep apnea (OSA) is defined by interrupted breathing during sleep due to a collapse of the soft tissues in the upper airway. It affects up to 25% of the adult population and is often overlooked as being an underlying cause for a number of pathological conditions. Although OSA has strong associations to cerebrovascular diseases including stroke and dementia, mechanisms that underlie the effects of OSA on endothelium and smooth muscle, the sites for cerebral blood flow (CBF) control, are unknown. The purpose of this proposal is to initiate studies required for understanding the pathological mechanisms associated with cerebrovascular dysfunction following OSA. One unique aspect of these studies involves our rat model of OSA. In this newly developed model, we will obstruct the airway during the sleep cycle in unanesthetized, freely- ranging rats. This model has several important features that more closely mimics OSA as it occurs in the human and will help to provide a more complete understanding of the pathological events associated with OSA in the cerebral circulation. We propose that ROS and endothelin act in a pathological cycle to produce a hypercontractile phenotype in cerebral arteries and arterioles. That is, during OSA, generation of ROS upregulates the endothelin pathway and the endothelin pathway generates ROS. Further, we propose that breaking this pathological cycle by either scavenging ROS or inhibiting the endothelin pathway will inhibit the pathological alterations in cerebral vessels. We will test the following hypothesis: During OSA a cycle between ROS generation and endothelin produces pathological alterations in the cerebrovascular wall and disrupts cerebral blood flow. We will test our hypothesis in three specific aims. (SA1) Determine if breaking the cycle between ROS and ET-1 by reducing ROS will alleviate the cerebrovascular dysfunction in arteries and arterioles in rats following 28 days of OSA. (SA2) Determine if breaking the cycle between ROS and ET-1 by blocking endothelin receptors will alleviate the cerebrovascular dysfunction in arteries and arterioles in rats following 28 days of OSA. (SA3) Determine if 28 days of OSA decreases CBF, attenuates the CBF response to whisker stimulation, attenuates autoregulation, or attenuates the CBF response to hypercapnia. Determine if reducing ROS and/or blocking endothelin receptors restores these responses in vivo. We will complete these specific aims using isolated pressurized cerebral arteries and arterioles and measurement of CBF with autoradiographic techniques and laser Doppler flowmetry. Completion of these studies will move us toward a better understanding of the underlying mechanisms of cerebrovascular dysfunction and towards more effective treatments to reduce the devastating effects of OSA on the cerebral circulation with a goal of reducing the incidence of stroke and the severity of dementias.
Obstructive sleep apnea is defined by interrupted breathing during sleep due to a collapse of the soft tissues in the upper airway. Although obstructive sleep apnea has strong associations to cerebrovascular diseases including stroke and dementia, mechanisms that underlie the effects of obstructive sleep apnea on endothelium and smooth muscle, the sites for cerebral blood flow control, are unknown. The purpose of this proposal is to initiate studies required for understanding the pathological mechanisms associated with cerebrovascular dysfunction following obstructive sleep apnea.
|Ganesh, Bhanu P; Nelson, James W; Eskew, Joshua R et al. (2018) Prebiotics, Probiotics, and Acetate Supplementation Prevent Hypertension in a Model of Obstructive Sleep Apnea. Hypertension 72:1141-1150|
|Spychala, Monica S; Venna, Venugopal Reddy; Jandzinski, Michal et al. (2018) Age-related changes in the gut microbiota influence systemic inflammation and stroke outcome. Ann Neurol 84:23-36|
|Adnan, Sareema; Nelson, James W; Ajami, Nadim J et al. (2017) Alterations in the gut microbiota can elicit hypertension in rats. Physiol Genomics 49:96-104|
|Durgan, David J; Crossland, Randy F; Bryan Jr, Robert M (2017) The rat cerebral vasculature exhibits time-of-day-dependent oscillations in circadian clock genes and vascular function that are attenuated following obstructive sleep apnea. J Cereb Blood Flow Metab 37:2806-2819|
|Durgan, David J; Ganesh, Bhanu P; Cope, Julia L et al. (2016) Role of the Gut Microbiome in Obstructive Sleep Apnea-Induced Hypertension. Hypertension 67:469-74|
|Durgan, David J; Crossland, Randy F; Lloyd, Eric E et al. (2015) Increased cerebrovascular sensitivity to endothelin-1 in a rat model of obstructive sleep apnea: a role for endothelin receptor B. J Cereb Blood Flow Metab 35:402-11|
|Lloyd, Eric E; Durgan, David J; Martini, Sharyl R et al. (2015) Pathological effects of obstructive apneas during the sleep cycle in an animal model of cerebral small vessel disease. Hypertension 66:913-7|
|Durgan, David J; Bryan, Robert M (2013) The same but different. J Cereb Blood Flow Metab 33:1485|
|Crossland, Randy F; Durgan, David J; Lloyd, Eric E et al. (2013) A new rodent model for obstructive sleep apnea: effects on ATP-mediated dilations in cerebral arteries. Am J Physiol Regul Integr Comp Physiol 305:R334-42|