Parenchymal arterioles (PAs) play a critical role in assuring that appropriate local cerebral blood flow and perfusion pressure are maintained under a variety of conditions. This essential physiological function is regulated by tight communication among the various cells that form the cerebrovascular unit (endothelium, smooth muscle, and astrocytes) and clearly involves the dynamic regulation of intracellular [Ca^""""""""*] in each cell type. The focus of this project is on parenchymal arteriolar smooth muscle cell calcium (Ca^*) signaling, which is the ultimate determinant of myocyte excitability, vasomotor tone, and blood flow in the microcirculation of the brain. Voltage-dependent Ca^* (Cav) channels are central integrators of both vasodilator and vasoconstrictor stimuli in the cerebral circulation. In addition, Transient Receptor Potential (TRP) channels transduce vasoactive signals, including intravascular pressure and receptor activation, to directly and indirectly modulate intracellular Ca^* in the vasculature. However, virtually nothing is known about the functional contributions of these channels in PAs. Thus the overarching goal of this project is to reveal the molecular mechanisms of vascular control of PAs involving Cav and TRP channels. Based on our preliminary data we have formulated a model of excitation-contraction coupling in arteriolar smooth muscle in which E-C coupling is facilitated in two ways: 1) High activity of Ca^* entry pathways mediated or modulated by Cav, TRPC6, TRPM4, and TRPV4 channels, and by PCK, and 2) suppressed negative feedback input normally provided by Ca^* spark and BK channel activity. To assess the specific roles of Cav and TRP channels in generating Ca^* signals, Ca^* will be measured with fluorescent dyes using confocal and TIRF microscopy, approaches developed or implemented by our team. Vasomotor function will be measured in isolated, pressurized parenchymal arteriole segments, and ion channel function will be studied using patch clamp approaches. Information and insights gained will be coordinated with studies focused on normal endothelial cell function in PAs (M. Nelson, Project 1) and used to understand how arteriolar smooth muscle function, in general, and the expression and activity of various vasoconstrictor mechanisms, in particular, may be altered following ischemia and reperfusion (M. Cipolla, Project 3) and subarachnoid hemorrhage (G. Wellman, Project 4). Elucidation of the roles of TRP channels and their interaction with Cav channels in smooth muscle function and dysfunction as detailed in this project represents a unique opportunity to define a new set of pharmacologically relevant drug targets aimed at treating and preventing cerebrovascular disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL095488-03
Application #
8381476
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$378,450
Indirect Cost
$106,050
Name
University of Vermont & St Agric College
Department
Type
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
Baylie, Rachael; Ahmed, Majid; Bonev, Adrian D et al. (2017) Lack of direct effect of adiponectin on vascular smooth muscle cell BKCa channels or Ca2+ signaling in the regulation of small artery pressure-induced constriction. Physiol Rep 5:
Hawkins, Virginia E; Takakura, Ana C; Trinh, Ashley et al. (2017) Purinergic regulation of vascular tone in the retrotrapezoid nucleus is specialized to support the drive to breathe. Elife 6:
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

Showing the most recent 10 out of 93 publications