The survival of neurons in the brain depends on an uninterrupted, dynamically regulated supply of blood- borne nutrients, which are delivered through a dense capillary network. Despite extensive study, the mechanisms underlying the functional linkage between neuronal demand and vascular supply, termed neurovascular coupling (NVC), remains poorly understood. Anatomically, intracerebral (parenchymal) arterioles form bottlenecks that precisely control cerebral hemodynamics, and capillary endothelial cells are ideally positioned to detect neuronal activity. We propose that prostaglandin E2 (PGE2), a suggested NVC mediator, acts at the level of capillaries to initiate a Ca2+ wave that travels along endothelial cells to reach the upstream arteriole, where it triggers vasodilation through endothelium-dependent hyperpolarization. Our extensive preliminary data also describe a capillary signaling complex between the epidermal growth factor receptor (EGFR) and transient receptor potential vanilloid 3 (TRPV3) channels that is involved in generating this PGE2-induce retrograde Ca2+ signal. Using a well-established genetic mouse model of CADASIL, a hereditary form of small vessel disease, we further propose that pathogenic mechanisms that result in EGFR pathway inhibition in smooth muscle also depress EGFR/TRPV3 signaling complex in capillaries, resulting in impaired NVC. To test these ideas, we engage a wide variety of novel, state-of-the-art experimental approaches using intact animals, native tissue and freshly isolated cells, complemented by sophisticated computational modeling.
Aim 1 will explore how capillary PGE2 and TRPV3 signaling generates retrograde Ca signals to 2+ cause upstream arteriolar dilation, taking advantage of our newly developed pressurized arteriole-capillary ex vivo preparation. Using extracellular matrix disruptions characteristic of CADASIL as a framework, Aim 2 will provide the first insights into the mechanisms by which TRPV3 channels and evoked upstream dilation are regulated by EGFR and its upstream regulators TIMP3, a matrix metalloproteinase inhibitor, and ADAM17, a metalloproteinase that mediates shedding of the EGFR ligand, HB-EGF. Building on our previous report that CADASIL causes voltage-gated K (KV) channel upregulation in arteriolar myocytes, Aim 3 will explore the + hypothesis that increased KV current density limits arteriolar conducted dilation, and thus NVC, initiated by capillary PGE2/TRPV3 signaling in CADASIL. The proposed work has the potential to revolutionize our understanding of communication within the brain microcirculation, and as such should provide the foundation for understanding small vessel diseases of the brain.

Public Health Relevance

Neurons in the brain have few energy reserves and therefore depend on local blood flow through arterioles and capillaries for a continuous supply of nutrients. Here we describe a novel signaling network engaging propagating calcium signals from the capillaries to the arterioles for efficient vasorelaxation and regulation of blood flow to provide a constant energy supply for active neurons. Small vessel diseases disrupt this mechanism by blunting capillary calcium signals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL136636-01
Application #
9291583
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Charette, Marc F
Project Start
2017-02-01
Project End
2022-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
1
Fiscal Year
2017
Total Cost
$400,844
Indirect Cost
$141,844
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
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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:
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