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Capillaries as a Sensory Web that Controls Cerebral Blood Flow in Health and Disease

Award Number: R35HL140027
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Capillaries as a Sensory Web that Controls Cerebral Blood Flow in Health and Disease - PROJECT SUMMARY Neurons in the brain have limited energy reserves and thus rely on a “just-in-time” delivery strategy in which active neurons signal to the brain microvasculature to increase regional cerebral blood flow (CBF), resupplying nutrients and oxygen as well as removing toxic metabolites. Despite extensive study, the mechanisms underlying the functional linkage between neuronal metabolic demand and vascular supply, termed neurovascular coupling (NVC), remain poorly understood. Blood flow to the brain is mediated by parenchymal arterioles and hundreds of miles of capillaries, which enormously extend the territory of perfusion. We recently presented evidence supporting the concept that brain capillaries act as a neuronal activity-sensing network, demonstrating that brain capillary endothelial cells (cECs) are capable of initiating an electrical (hyperpolarizing) signal in response to neuronal activity that propagates upstream to cause dilation of feeding arterioles and increase blood flow locally at the site of signal initiation. We have established the mechanistic basis for this electrical signal, showing that neuron- and/or astrocyte-derived potassium (K+) is the critical mediator and identifying the strong inward rectifier K+ channel, Kir2.1, as the key molecular player. We have recently discovered that a second fundamental NVC mechanism based on calcium (Ca2+) signaling, with distinct kinetics and regulatory features, also operates in brain capillaries, and can be initiated by the putative NVC mediator prostaglandin E2 (PGE2). We have further found that a mechanism initiated by Gq-protein coupled receptor signaling and mediated by dynamic changes in membrane phosphatidylinositol 4,5- bisphosphate (PIP2) levels controls the balance between electrical and Ca signaling. Additional preliminary 2+ data support a role for gasotransmission via Ca2+-dependent endothelial nitric oxide signaling and pericyte- mediated regulation of capillary blood flow in modulating NVC. The immediate goals of this proposal are to create an integrated view of electrical, Ca2+ and related regulatory signaling mechanisms at molecular, biophysical, and computational-modeling levels by examining their operation in increasingly complex segments of the brain vasculature ex vivo, in vivo, and in silico. Ultimately, we propose to weave these research threads together to create a systems-level view of physiological capillary-to-arteriole/pial artery signaling in the brain, and test the concept that gradual degradation of this sensory web and the attendant progressive decay of cerebrovascular function contributes to small vessel diseases of the brain.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $905,963 )
2025	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	001	7	8/5/2025	NON-COMPETING CONTINUATION	$90,595
2025	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	000	7	11/22/2024	NON-COMPETING CONTINUATION	$815,368
														Subtotal = $905,963

Issue Date FY: 2024 ( Subtotal = $887,845 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	001	6	6/8/2024	NON-COMPETING CONTINUATION	$72,477
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	000	6	12/18/2023	NON-COMPETING CONTINUATION	$815,368
														Subtotal = $887,845

Issue Date FY: 2023 ( Subtotal = $905,963 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	000	5	12/16/2022	NON-COMPETING CONTINUATION	$815,368
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	001	5	3/3/2023	NON-COMPETING CONTINUATION	$90,595
														Subtotal = $905,963

Issue Date FY: 2022 ( Subtotal = $905,963 )
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	001	4	6/17/2022	NON-COMPETING CONTINUATION	$90,595
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	000	4	12/15/2021	NON-COMPETING CONTINUATION	$815,368
														Subtotal = $905,963

Issue Date FY: 2021 ( Subtotal = $905,963 )
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	002	3	5/24/2021	NON-COMPETING CONTINUATION	$90,596
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	001	3	11/20/2020	NON-COMPETING CONTINUATION	$815,367
2021	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	000	2	11/5/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $905,963

Issue Date FY: 2020 ( Subtotal = $905,963 )
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	000	2	1/13/2020	NON-COMPETING CONTINUATION	$860,665
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	001	2	3/13/2020	NON-COMPETING CONTINUATION	$45,298
														Subtotal = $905,963

Issue Date FY: 2019 ( Subtotal = $919,963 )
2019	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Cardiovascular Diseases Research	000	1	12/28/2018	NEW	$919,963
														Subtotal = $919,963

Grand Total All Awards = $6,337,623

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Capillaries as a Sensory Web that Controls Cerebral Blood Flow in Health and Disease

Award Number: R35HL140027

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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