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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS080531-02
Application #
8463640
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
He, Janet
Project Start
2012-05-01
Project End
2017-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
2
Fiscal Year
2013
Total Cost
$330,362
Indirect Cost
$119,268
Name
Baylor College of Medicine
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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
Durgan, David J; Bryan, Robert M (2013) The same but different. J Cereb Blood Flow Metab 33:1485