The vascular endothelium in parenchymal (intracerebral) arterioles is a critical mediator of normal cerebral function, serving as both a physical barrier and a modulator of blood flow within the brain. Ca2+ signaling and the Ca2+sensitive K+ channels, IK and SK, and TRPV4 in endothelial cells (ECs) activate pathways that transmit vasoregulatory signals to adjacent smooth muscle (SM) and along the endothelial lining of blood vessels. These signals may also communicate to nearby astrocytes and neurons to modulate neurovascular coupling (NVC). Despite the importance of parenchymal arteriolar (PA) endothelium, little is known about its control of vascular tone or potential influence on NVC in the brain.
Aim 1 will elucidate the properties and roles of endothelial Ca2+ signaling modalities and IK, SK and TRPV4 channels in PA ECs using a novel mouse model that expresses a Ca2+ biosensor (GCaMP2) in the endothelium. Exploiting these GCaMP2 mice, we have recently discovered a localized, stationary IPs-mediated Ca2+ signal in endothelial projections to the SM. This signal, termed a """"""""pulsar"""""""", activates co-localized IK channels to modulate vascular tone.
Aim 2 will determine the impact of endothelial function on the SM of PAs, exploring Ca2+ signaling, membrane potential and vascular diameter.
Aim 3 builds on Aims 1 &2 to explore the role of the endothelium in the context of the brain, evaluating its effects on NVC and blood flow using a novel approach based on simultaneous measurement of astrocytic endfoot Ca2+ and vascular responses. The proposed project will provide signiflcant new insight into endothelial function and communication to SM in PAs. Close collaboration between Projects 1 and 2 will assure appropriate consideration of the physiological interactions and communication between endothelium and smooth muscle in PAs. In conjunction with Projects 3 and 4, Project 1 will help illuminate the role of the endothelium under the clinically important pathological conditions of ischemia/reperfusion injury and subarachnoid hemorrhage. This project should reveal novel targets involved in modulating blood flow in the brain and suggest therapeutic agents that do not require passage through the blood brain barrier.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL095488-04
Application #
8514689
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2013
Total Cost
$367,378
Indirect Cost
$123,474
Name
University of Vermont & St Agric College
Department
Type
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Harraz, Osama F; Longden, Thomas A; Hill-Eubanks, David et al. (2018) PIP2 depletion promotes TRPV4 channel activity in mouse brain capillary endothelial cells. Elife 7:
Gomes, Carolina Cavalieri; Gayden, Tenzin; Bajic, Andrea et al. (2018) TRPV4 and KRAS and FGFR1 gain-of-function mutations drive giant cell lesions of the jaw. Nat Commun 9:4572
Harraz, Osama F; Longden, Thomas A; Dabertrand, Fabrice et al. (2018) Endothelial GqPCR activity controls capillary electrical signaling and brain blood flow through PIP2 depletion. Proc Natl Acad Sci U S A 115:E3569-E3577
Koide, Masayo; Moshkforoush, Arash; Tsoukias, Nikolaos M et al. (2018) The yin and yang of KV channels in cerebral small vessel pathologies. Microcirculation 25:
Balbi, Matilde; Koide, Masayo; Schwarzmaier, Susanne M et al. (2017) Acute changes in neurovascular reactivity after subarachnoid hemorrhage in vivo. J Cereb Blood Flow Metab 37:178-187
Li, Yao; Brayden, Joseph E (2017) Rho kinase activity governs arteriolar myogenic depolarization. J Cereb Blood Flow Metab 37:140-152
Syed, Arsalan U; Koide, Masayo; Brayden, Joseph E et al. (2017) Tonic regulation of middle meningeal artery diameter by ATP-sensitive potassium channels. J Cereb Blood Flow Metab :271678X17749392
Balbi, Matilde; Koide, Masayo; Wellman, George C et al. (2017) Inversion of neurovascular coupling after subarachnoid hemorrhage in vivo. J Cereb Blood Flow Metab 37:3625-3634
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:
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:

Showing the most recent 10 out of 103 publications