# Molecular Genetic Dissection of Fenestrated Vascular Development in the Choroid Plexus

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2021 · $378,350

## Abstract

PROJECT SUMMARY/ABSTRACT
Cerebrovascular diseases remain a leading cause of serious long-term disability. Many of these diseases
originate, at least in part, from genetic defects that impact the development and maturation of blood vessels in
the central nervous system (CNS) and meninges. Despite substantial progress in our understanding of CNS
angiogenesis and barriergenesis, our knowledge of the highly permeable, or fenestrated, microvasculature
formed in the choroid plexus (CP) and circumventricular organs remains limited. The overall goal of this
proposal is to fill this gap in scientific knowledge by understanding the molecular genetic mechanisms of
fenestrated brain vascular development, specifically focusing on the CP. We recently found that CP
vascularization in zebrafish requires a unique angiogenic mechanism whereby zebrafish vascular endothelial
growth factor (Vegf) orthologs, specifically Vegfab and Vegfc, play a functionally redundant role. Surprisingly,
this mechanism is specific to CP vascularization, since the neighboring non-fenestrated brain vasculature is
not affected in the vegfab;vegfc double mutants. These results led us to formulate a paradigm-shifting
hypothesis that fenestrated CP and non-fenestrated brain vascular development requires distinct sets of the
Vegf/Vegfr codes and signaling. Given the critical roles for Vegfs in diverse pathophysiological processes and
also the fact that no molecular cue that drives CP vascularization has been reported in any vertebrate species,
the results of this study will have a significant positive impact on the fields of CP physiology and vascular
biology beyond CP vascularization. Our further genetic, pharmacological, and expression data propose a
model in which paracrine Vegfab from CP epithelial cells and autocrine Vegfc from the endothelium together
controls CP vascularization via PI3K and ERK signaling pathways. The following two Specific Aims are
proposed to test our hypotheses. Aim 1 will test the hypothesis that fenestrated CP and non-fenestrated brain
vascular development requires distinct Vegf/Vegfr codes and signaling. Aim 2 will test the hypothesis that the
spatiotemporal coordination of paracrine Vegfab from CP epithelial cells and autocrine Vegfc from the
endothelium together drives fenestrated CP vascular development. We will pursue these aims by combining
novel zebrafish molecular genetic tools with advanced imaging technologies and genetic mosaic analyses. The
proposed work is an innovative molecular genetics study in this field because it exploits various strengths of
the zebrafish model to overcome technical limitations and address the following fundamental processes: 1) the
cellular and molecular basis of fenestrated CP vascular development; and 2) the developmental mechanisms
behind the formation of heterogeneous brain vascular networks. Mechanistic information gleaned from this
work will shed new light on potential molecular pathways involved in the pathogenesis of ...

## Key facts

- **NIH application ID:** 10249986
- **Project number:** 5R01NS117510-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Ryota Matsuoka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $378,350
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10249986

## Citation

> US National Institutes of Health, RePORTER application 10249986, Molecular Genetic Dissection of Fenestrated Vascular Development in the Choroid Plexus (5R01NS117510-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10249986. Licensed CC0.

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