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Targeting Pial Collaterals for Acute Stroke Treatment

Award Number: R01NS093289
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2015
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Targeting Pial Collaterals for Acute Stroke Treatment - The cerebral pial collateral circulation is the most important predictor of outcome from acute ischemic stroke. Patients with good collateral status on imaging at the time of occlusion have more salvageable tissue, smaller ischemic cores, and better neurological outcome after large vessel occlusion (LVO). In contrast, patients with poor collaterals have worse outcome even if recanalization is achieved. Pial collaterals are a network of leptomeningeal anastomoses (LMAs) that maintain perfusion to the penumbra, a region with constrained blood supply that is potentially salvageable if reperfusion occurs. Our overall goal is to understand the function of LMAs and develop treatments that sustain or increase penumbral flow during LVO, especially under conditions that have poor collateral perfusion such as chronic hypertension. Our previous study found that LMAs from spontaneously hypertensive rats (SHR) were highly vasoconstricted and responded to pressure with robust myogenic constriction that persisted in vivo during middle cerebral artery occlusion (MCAO) used to mimic LVO. This was in contrast to LMAs from normotensive Wistar rats that were more vasodilated and had little basal tone. Our central hypothesis is that hypertension promotes vasoconstriction of LMAs and impairs flow-mediated dilation that limits perfusion to the penumbra during LVO. Our preliminary and published data support a role for angiotensin II (Ang II) and plasminogen activated inhibitor-1 (PAI-1) as underlying mechanisms of hypertension- induced vasoconstriction of LMAs through direct inhibition of endothelial nitric oxide synthase (eNOS). Aim 1 will determine the role of Ang II, PAI-1 and the transient receptor potential vanilliod 4 (TRPV4), a shear stress- responsive ion channel, in mediating collateral flow in normotensive and hypertensive male and female rats. We will also investigate mechanisms of impaired collateral flow and LMA dysfunction during chronic hypertension. Our preliminary data also found that induced hypertension – acutely increasing blood pressure to enhance collateral perfusion during LVO – increased collateral flow in normotensive rats that was limited in SHR, likely due to vasoconstricted LMAs. However, vasodilation with a PAI-1 inhibitor increased collateral flow in SHR, leading us to hypothesize that treatment to dilate LMAs during occlusion will improve collateral flow and extend the time window for reperfusion in SHR. Therefore Aim 2 is to determine the efficacy of induced hypertension and vasodilation as collateral therapeutics on outcome from LVO. We will use the mechanistic information gained under Aim 1 to guide Aim 2 and test clinically relevant treatments on penumbral perfusion, oxygenation and long- term outcome from LVO. The results of this project will provide valuable information on the function of pial collaterals that are central to stroke treatment and outcome from LVO.


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: 2026 ( Subtotal = $400,450 )
2026	2026	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	12/9/2025	NON-COMPETING CONTINUATION	$400,450
														Subtotal = $400,450

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	4/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $431,596 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	3/18/2024	NON-COMPETING CONTINUATION	$400,450
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	4/9/2024	NON-COMPETING CONTINUATION	$31,146
														Subtotal = $431,596

Issue Date FY: 2023 ( Subtotal = $444,945 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	3/7/2023	NON-COMPETING CONTINUATION	$444,945
														Subtotal = $444,945

Issue Date FY: 2022 ( Subtotal = $480,395 )
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	7	4/4/2022	NON-COMPETING CONTINUATION	$48,043
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	3/15/2022	NON-COMPETING CONTINUATION	$432,352
2022	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	11/14/2021	COMPETING CONTINUATION	$25,989
2022	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/14/2021	NON-COMPETING CONTINUATION	-$25,989
														Subtotal = $480,395

Issue Date FY: 2021 ( Subtotal = $455,761 )
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	5/26/2021	COMPETING CONTINUATION	$455,761
2021	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/16/2021	NON-COMPETING CONTINUATION	$0
2021	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/18/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $455,761

Issue Date FY: 2019 ( Subtotal = $341,250 )
2019	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/19/2019	NON-COMPETING CONTINUATION	$341,250
														Subtotal = $341,250

Issue Date FY: 2018 ( Subtotal = $341,250 )
2018	2018	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/24/2018	NON-COMPETING CONTINUATION	$341,250
														Subtotal = $341,250

Issue Date FY: 2017 ( Subtotal = $341,250 )
2017	2017	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/12/2017	NON-COMPETING CONTINUATION	$307,125
2017	2017	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/25/2017	NON-COMPETING CONTINUATION	$34,125
														Subtotal = $341,250

Issue Date FY: 2016 ( Subtotal = $334,202 )
2016	2016	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/25/2016	NON-COMPETING CONTINUATION	$334,202
														Subtotal = $334,202

Issue Date FY: 2015 ( Subtotal = $330,733 )
2015	2015	UNIVERSITY OF VERMONT	223 WATERMAN BUILDING	BURLINGTON	VT	05405	CHITTENDEN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/24/2015	NEW	$330,733
														Subtotal = $330,733

Grand Total All Awards = $3,901,832

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Targeting Pial Collaterals for Acute Stroke Treatment

Award Number: R01NS093289

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2015

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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