# Endothelial-Pericyte Crosstalk in Diabetic Stroke

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $417,539

## Abstract

Project Summary
Tissue plasminogen activator (tPA) remains the only FDA-approved therapy for acute ischemic stroke.
Unfortunately, one-third to half of patients with successful recanalization of large cerebral vessels do not have
good clinical outcome. This is in part due to incomplete microvascular reperfusion termed focal “no-reflow”, which
is particularly prevalent in diabetic stroke. The current proposal will determine the role of endothelial-pericyte
crosstalk, mediated by the action of the endothelial eicosanoids epoxyeicosatrienoates (EETs) on pericytes, in
microvascular no-reflow after diabetic stroke in mice. We will test the hypothesis that endothelial-derived EETs
preserve capillary perfusion in brain after ischemia, in part by protecting pericytes from ischemic injury, and that
diabetes reduces microvascular endothelial EETs; thus, leading to greater pericyte injury and capillary damage
after diabetic stroke. We will also determine if EETs protect pericytes by inhibiting G-protein coupled receptor 39
(GPR39). Stroke is induced in mice with and without type 2 diabetic (T2D), and with higher or lower endothelial
EETs (due to transgenic overexpression or deletion of EETs-degrading enzyme soluble epoxide hydrolase, sEH,
in endothelium) using an intraluminal occlusive filament or in-situ thrombin injection to occlude the middle
cerebral artery (MCA). Intra-vital imaging using optical microangiography (OMAG) and two-photon microscopy
(2PM) will be used to assess pericyte morphology, BBB integrity, capillary blood flow, and platelet and leukocyte
morphology and dynamics within the peri-infarct region in-vivo, in real-time after MCA occlusion. Mice will be
survived for 4 days after stroke to assess cellular and tissue damage (H&E, EM, IHC), and for 28 days to assess
long-term functional deficit (neurocognitive and somatosensory). We propose that preserving endothelial-
pericyte EETs/GPR39 signaling protects pericytes, prevents no-reflow and reduces brain tissue damage and
neurobehavioral functional deficit. Enhancing endothelial EETs, either pharmacologically or in transgenic mice
with higher endothelial EETs, will also enhance tPA efficacy and reduce tPA-associated hemorrhage after stroke
in diabetic mice.

## Key facts

- **NIH application ID:** 10109161
- **Project number:** 5R01NS108501-04
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Nabil J Alkayed
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,539
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10109161

## Citation

> US National Institutes of Health, RePORTER application 10109161, Endothelial-Pericyte Crosstalk in Diabetic Stroke (5R01NS108501-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10109161. Licensed CC0.

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