This Program, consisting of four Projects and three Cores, focuses on parenchymal (intracerebral) arterioles, which distribute blood within the brain and exhibit unique, albeit poorly understood, properties. The overall goal Is to elucidate the molecular mechanisms by which the endothelium and smooth muscle (SM) of parenchymal arterioles (PAs) regulate vascular tone and neurovascular coupling (NVC) normally, and following ischemia/reperfusion (l/R) injury and subarachnoid hemorrhage (SAH). The central unifying theme is that the precise control of Ca^* signaling in cells composing the """"""""cerebrovascular unit""""""""? endothelium, SM and astrocytes?determines normal brain function;by extension, dysfunction of Ca^* signaling dynamics contributes to cerebrovascular disorders. Each project studies overlapping elements of the biological system to form a whole. Project 1 will provide the first information on properties and function of PA endothelial cells (ECs), exploring Ca^* signaling and Ca^*-sensitive SK and IK potassium channels and their impact on SM function and NVC. Project 2 will focus on parenchymal arteriolar SM, with an emphasis on voltage-dependent Ca^* channels (Cav) and transient receptor potential (TRP) channels. Projects 1 and 2 provide the platform for Projects 3 and 4. Project 3 will interact with Projects 1 and 2 to explore the underlying mechanistic basis for the profound changes in parenchymal arteriolar reactivity that develop following i/R, focusing on EC-SM changes in ion channel functionality. Project 4, which focuses on PAs and NVC following SAH, intersects with Project 2 on the effects of SAH on SM Cav and TRP channels, and with Project 1 on endothelial function and NVC. Because the endothelium and SM function physiologically as one entity, Projects 1 and 2 are inherently highly interdependent. Projects 3 and 4, which focus on dysregulation of cerebrovascular unit function under two divergent, but clinically relevant, pathological conditions, depend on information derived from Projects 1 and 2. The Imaging Core will provide state-of-the-art approaches for Ca^* measurements in complex systems. The Animal and Instrumentation Core will consolidate and coordinate all animal and in vivo work, including the development of novel genetically encoded, ratiometric Ca^* biosensors. The long-term objective is to understand blood flow in the brain in health and disease, and by doing so, to reveal exciting novel targets that can be exploited in the treatment of cerebrovascular disease.

Public Health Relevance

This Program focuses on the small arteries within the brain, which are responsible for the moment-to moment health of the brain. Despite their importance, little is known about these arteries in health and disease. The Program will elucidate how these arteries function normally and after stroke and bleeding in the brain, and in doing so will reveal new therapeutic approaches to treat blood vessel disorders in the brain.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
3P01HL095488-03S1
Application #
8515613
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Charette, Marc F
Project Start
2010-08-01
Project End
2015-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$42,317
Indirect Cost
$14,568
Name
University of Vermont & St Agric College
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Villalba, Nuria; Sackheim, Adrian M; Nunez, Ivette A et al. (2017) Traumatic Brain Injury Causes Endothelial Dysfunction in the Systemic Microcirculation through Arginase-1-Dependent Uncoupling of Endothelial Nitric Oxide Synthase. J Neurotrauma 34:192-203
Longden, Thomas A; Dabertrand, Fabrice; Koide, Masayo et al. (2017) Capillary K+-sensing initiates retrograde hyperpolarization to increase local cerebral blood flow. Nat Neurosci 20:717-726
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Capone, Carmen; Dabertrand, Fabrice; Baron-Menguy, Celine et al. (2016) Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics. Elife 5:
Linfante, Italo; Cipolla, Marilyn J (2016) Improving Reperfusion Therapies in the Era of Mechanical Thrombectomy. Transl Stroke Res 7:294-302
Ahnstedt, Hilda; McCullough, Louise D; Cipolla, Marilyn J (2016) The Importance of Considering Sex Differences in Translational Stroke Research. Transl Stroke Res 7:261-73
Ahnstedt, Hilda; Sweet, Julie; Cruden, Patrick et al. (2016) Effects of Early Post-Ischemic Reperfusion and tPA on Cerebrovascular Function and Nitrosative Stress in Female Rats. Transl Stroke Res 7:228-38
Heppner, Thomas J; Tykocki, Nathan R; Hill-Eubanks, David et al. (2016) Transient contractions of urinary bladder smooth muscle are drivers of afferent nerve activity during filling. J Gen Physiol 147:323-35
Canavero, Isabella; Sherburne, Helene A; Tremble, Sarah M et al. (2016) Effects of Acute Stroke Serum on Non-Ischemic Cerebral and Mesenteric Vascular Function. Transl Stroke Res 7:156-65

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