# Unraveling the role of tPA in the neurovascular unit

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $661,256

## Abstract

PROJECT SUMMARY
Stroke is a significant cause of adult disability in the US. Early treatment with thrombolytics or mechanical
thrombectomy can significantly improve neurological outcomes in patients with acute ischemic stroke.
However, following these acute interventions long term recovery care is primarily limited to treatments
designed to prevent stroke recurrence, and to rehabilitation therapies. Factors that can influence long term
prognosis, include age, stroke severity, infarct location, and comorbidities. Many stroke survivors do not
recover full function for normal activities with ~45% of working age adults unable to return to work by 6 to 12
months following stroke. Thus, a major challenge for stroke treatment is the identification of therapeutic
strategies that can help restore function and limit long term disability. In studies conducted in previous cycles of
this grant we have focused on understanding the pathways affecting acute stroke injury. We demonstrated that
during ischemic stroke, tissue plasminogen activator (tPA) acts on the parenchymal side of the neurovascular
unit (NVU) to increase blood brain barrier (BBB) permeability and symptomatic intracerebral hemorrhage
(sICH). Studies established that tPA cleavage releases an inhibitory domain activating platelet derived growth
factor-C (PDGFC) signaling through the PDGF-receptor-α (PDGFRα) in perivascular astrocytes ultimately
leading to downstream signaling by vascular endothelial cell growth factor (VEGF) and PKCβ in vascular
endothelial cells (ECs) regulating the tight junction complex through occludin phosphorylation. Our long-term
goal is to understand the molecular pathways activated during ischemic stroke and to identify interventions
that make stroke treatment safer and more effective. In this application we will build on these data and
examine the role of the tPA/PDGFRα/VEGF/PKCβ pathway in post-stroke neuroinflammation, and on the
downstream recovery pathways. Our central hypothesis is that in ischemic stroke tPA-mediated early events
in the NVU control both neuroinflammation and post-stroke recovery of brain function. We will test this
hypothesis in three specific aims that will identify the molecular mechanisms of this pathway during early post-
stroke neuroinflammation and on the resolution of neuroinflammation during the transition to healing and the
restoration of cerebral blood flow to the damaged brain tissue. Together, these studies will elucidate
mechanisms by with tPA controls both inflammation and collateral vessel growth and identify potential
interventions to promote long term functional recovery.

## Key facts

- **NIH application ID:** 10899880
- **Project number:** 2R01HL055374-24A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David Antonetti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $661,256
- **Award type:** 2
- **Project period:** 1995-08-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10899880

## Citation

> US National Institutes of Health, RePORTER application 10899880, Unraveling the role of tPA in the neurovascular unit (2R01HL055374-24A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10899880. Licensed CC0.

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