# Unraveling the role of tPA in the neurovascular unit

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $600,694

## Abstract

ABSTRACT
Treatment of acute ischemic stroke with tPA can significantly improve neurological outcomes. However, many
patients do not recanalize with one recent study showing that only 53% of patients receiving IV tPA were
recanalized at 24 hours. And while endovascular therapy can significantly increase reperfusion rates in
patients with large vessel disease, not all occlusions are accessible for endovascular treatment and many
community hospitals are not able to perform these procedures. Thus, for many patients thrombolysis remains
the only treatment option. In addition to the limited efficacy of tPA, thrombolysis carries a small but significant
risk of symptomatic intracerebral hemorrhage (sICH), increasing from ~0.5% in untreated patients to up to 5%
in some studies. Importantly, the risk of fatal ICH with thrombolysis rises to ~2% in patients treated with the
current recommended dose of tPA. Studies with lower doses of tPA show a reduction in sICH however these
studies have not demonstrated noninferiority of the lower dose compared to standard therapy. In contrast to
stroke, dosing recommendations of thrombolytic tPA for myocardial infarction or pulmonary embolism can be
nearly 2-fold higher than the dose for ischemic stroke, suggesting that the balance between safety and efficacy
in stroke may limit the potential efficacy of tPA. Thus, understanding the molecular pathways triggered by
thrombolytic tPA that increase the incidence of hemorrhagic conversion could profoundly improve the
treatment of ischemic stroke. By targeting these pathways and reducing the risk of sICH it should be possible
to not only make thrombolysis safer but also to make it more effective by permitting increased doses of tPA to
be used to promote reperfusion in more patients.
 In earlier work, we established an association between tPA–mediated cell signaling in the neurovascular
unit (NVU) and blood brain barrier (BBB) regulation. Acting through tPA cleavage and activation of platelet-
derived growth factor C (PDGF-C) and binding of active PDGF-C to the PDGF receptor α (PDGFRα) on
perivascular astrocytes, this pathways induces increased vascular permeability and thrombolysis associated
hemorrhage. In the present application we present data demonstrating that tPA mediated PDGFRα signaling in
perivascular astrocytes enhances the activity of VEGF-A in the neurovascular unit leading to BBB breakdown
through disruption of endothelial cell tight junction complexes. This hypothesis is based upon strong
preliminary data linking tPA to the phosphorylation of the tight junction protein occludin at S490 and to
increased BBB permeability. This activity is dependent on PKCβ, and inhibition PKCβ or expression of a non-
phosphorylatable occludin mutant, significantly reduces thrombolytic tPA-associated ICH in a murine model of
thrombotic stroke with thrombolysis.

## Key facts

- **NIH application ID:** 10441490
- **Project number:** 5R01HL055374-23
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** David Antonetti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $600,694
- **Award type:** 5
- **Project period:** 1995-08-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10441490

## Citation

> US National Institutes of Health, RePORTER application 10441490, Unraveling the role of tPA in the neurovascular unit (5R01HL055374-23). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10441490. Licensed CC0.

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