# Endothelial tip cell-mediated angiogenesis and repair after neonatal stroke

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $467,912

## Abstract

PROJECT SUMMARY/ABSTRACT
Neonatal stroke is an important cause of death and disability, and diagnosis is often delayed. There is
insufficient knowledge regarding repair mechanisms that occur in response to focal ischemia-reperfusion injury
that is the most common cause of early stroke. Angiogenesis, fibrosis, and perivascular cell repopulation occur
in close proximity, with paracrine signaling supporting endothelial cell interactions that are vital for repair.
Modulating this neurovascular niche may be a potential target for enhancing outcomes after ischemic injury in
the developing brain. Erythropoietin and cell-based therapies have emerged as promising delayed treatment
strategies for stroke, although the mechanism of their benefit is still not entirely clear. It is likely that dynamic
release of pro-angiogenic growth factors and activation of signaling pathways downstream of erythropoietin
receptor have differential effects on endothelial cell subtypes in distinct brain regions and at different time
points after injury. In addition, the defined role of local fibrosis in injury progression and repair following early
focal brain injury is unknown. Effectively inducing long-term, functional angiogenesis requires understanding
and mimicking mechanisms that occur in the developing brain. Our objectives are to understand local
angiogenesis and fibrosis in ischemic and peri-infarct regions following focal ischemia-reperfusion
injury in the developing brain, and to determine the mechanisms of regeneration and repair with
delayed erythropoietin by focusing on the vascular response. In Aim 1, we will test the hypothesis that
endothelial tip cells at the vascular front are critical for angiogenesis following neonatal stroke, and that
delayed erythropoietin will enhance angiogenesis and alter endothelial cell-subtype gene expression profiles to
promote tip cell programs. In Aim 2, we will quantify fibroblasts and perivascular cells in the ischemic core and
peri-infarct penumbra in the acute, subacute, and chronic stages after stroke and determine how erythropoietin
signaling impacts local fibrosis and repair. Finally, in Aim 3, we will determine and modify specific signaling
pathways to test the hypothesis that dynamic endothelial cell signaling modulated by erythropoietin is crucial
for promoting local angiogenesis following focal brain injury. This will determine critical, modifiable pathways
important for injury progression and repair following neonatal stroke. Our primary hypothesis is that delayed
erythropoietin treatment will promote vascular growth and remodeling, reduce subacute fibrosis and
astrocytic proliferation in the ischemic core, and enhance perivascular signaling to improve
histological and functional outcomes after neonatal stroke. Together, these three aims will explore the
roles of specific cellular subtypes and pathways in recovery after focal brain injury, with the broader goal of
optimizing therapeutic strategies to improve long-ter...

## Key facts

- **NIH application ID:** 10585348
- **Project number:** 2R01NS107039-05A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Fernando Francisco Gonzalez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $467,912
- **Award type:** 2
- **Project period:** 2022-09-22 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10585348

## Citation

> US National Institutes of Health, RePORTER application 10585348, Endothelial tip cell-mediated angiogenesis and repair after neonatal stroke (2R01NS107039-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10585348. Licensed CC0.

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