# Astrocyte-specific molecular cues guiding retinal angiogenesis

> **NIH NIH F32** · DUKE UNIVERSITY · 2024 · $81,892

## Abstract

ABSTRACT
Angiogenesis is a central event in nervous system development that requires further elucidation within the
context of the retina. In normal development, retinal angiogenesis initiates from the optic nerve and proceeds
along the innermost layer of retina consisting of retinal nerve fibers and the developing astrocytic network.
Astrocytic development occurs prior to angiogenesis and is critical for guiding the developing vasculature.
Specialized endothelial cells called tip cells crawl along the astrocytes as the angiogenic wavefront advances,
so that the vasculature matches the pattern of astrocyte arbors. It is well understood that astrocytes secrete
VEGF-A in hypoxic zones to initiate angiogenesis, but the signals that advance the wavefront, and guide tip cells
along the astrocyte template, are unknown. The objective of this proposed study is to identify novel astrocyte-
derived molecular cues that guide retinal vascularization. The central hypothesis is that astrocytes provide
molecular cues that promote angiogenesis by 1) enhancing tip cell production; and 2) guiding tip cell growth so
that vasculature adopts the pattern of the astrocyte network. The rationale for this work is to provide a deeper
understanding of glial-mediated regulation of angiogenesis that may be applicable to the entire nervous system
while also providing candidate molecules to target in retinal pathologies such as retinopathy of prematurity
(ROP). The specific aims are: 1) Identify astrocyte-derived cues driving progression of the angiogenic
wavefront. Adrenomedullin (ADM) is a secreted peptide that was previously found to mediate angiogenesis via
its receptor, calcitonin receptor-like receptor (CLR) in conjunction with receptor activity modifying protein,
RAMP2, which are expressed by endothelial cells. Preliminary single-cell RNA-seq data shows that the
adrenomedullin gene is highly expressed by immature astrocytes. To test this, its angiogenic properties will be
tested utilizing a functional assay that consists of analyzing vasculature wavefront progression in cultured mouse
retinal explants that shall be co-cultured with ADM-expressing HEK293 cells. 2) Identify astrocyte-derived
cues that pattern growing vessels. Genes selectively expressed by astrocytes are candidates to guide tip cell
growth and angiogenesis. To identify such molecules, each cell type in the nerve fiber layer will be purified for
scRNA-seq. Astrocyte-specific genes encoding cell-surface or secreted molecules will be identified
bioinformatically. As in Aim 1, a functional assay using retinal explants will be used to test angiogenic capabilities
of putative tip cell-guiding astrocyte-specific genes. Completion of this work will be significant because it will
reveal novel components and drivers of angiogenesis expressed preferentially by astrocytes in the retina. Such
information will elucidate basic mechanisms of retinal angiogenesis, while also pinpointing important molecular
cues that may b...

## Key facts

- **NIH application ID:** 10877683
- **Project number:** 5F32EY035119-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Juan Valdez-Lopez
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $81,892
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877683

## Citation

> US National Institutes of Health, RePORTER application 10877683, Astrocyte-specific molecular cues guiding retinal angiogenesis (5F32EY035119-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877683. Licensed CC0.

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