# Targeting pial collaterals for acute stroke treatment

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $455,761

## Abstract

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.

## Key facts

- **NIH application ID:** 10309056
- **Project number:** 2R01NS093289-06
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Marilyn J Cipolla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $455,761
- **Award type:** 2
- **Project period:** 2015-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10309056

## Citation

> US National Institutes of Health, RePORTER application 10309056, Targeting pial collaterals for acute stroke treatment (2R01NS093289-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10309056. Licensed CC0.

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