# Roles of Nogo-B receptor in maintaining the structural integrity of blood vessels

> **NIH NIH R01** · NYU WINTHROP HOSPITAL · 2020 · $512,759

## Abstract

PROJECT ABSTRACT
Cerebral cavernous malformations (CCMs), which can occur in 1 out of every 200 people in the US, cause
seizure and cerebral hemorrhage. Previous studies have shown that decreased expression or a loss-of-function
mutation of CCM family genes (CCM1, CCM2, CCM3) causes CCMs. Although the genetic origins of familial
CCMs (20% of cases) have been well characterized, the etiology of sporadic CCMs (80% of cases) that do not
carry a germline mutation in CCM genes remains to be established. The long-term goal of our research is to
determine if and the extent to which Nogo-B receptor (NgBR) deficiency plays a causal role in the etiology of
sporadic CCMs. Support for this idea comes from our previous R01-funded studies where we not only elucidated
the molecular mechanisms by which NgBR binds farnesylated Ras to promote angiogenesis but also identified
that the NgBR-mediated Ras pathway regulates the expression and activation of transcription factors in
endothelial cells. Interestingly, these transcription factors have their binding elements in the promoter regions of
CCM1 and CCM2 genes. Consequently, transcript levels of CCM1 and CCM2 genes decrease in NgBR-deficient
human brain endothelial cells in vitro and in the yolk sac of NgBR endothelial cell-specific knockout (ecKO) mice
in vivo. Additional support of the NgBR-CCM connection comes from histology studies showing that NgBR
immunostaining intensity is significantly decreased in endothelial cells (ECs) of human sporadic CCM lesion
tissue sections. NgBR ecKO mice have aberrant patterns of cerebral blood vessel assembly, which results in
defective EC polarization and the formation of dilated blood vessels. This phenotype is surprisingly similar to the
CCM lesions. In addition, the pericyte layer around blood vessels in NgBR ecKO mice is much thinner than
littermate control mice. This means that endothelial NgBR deficiency can actually impair pericyte recruitment,
which is known as essential for maintaining the structural integrity of blood vessels. Based on these findings, we
hypothesize that the NgBR-Ras signaling pathway regulates CCM1/2 expression, and that disrupting this
signaling pathway results in cerebrovascular malformation. We will test this hypothesis in three aims. Aim 1:
Determine the role of the NgBR-CCM1/2 axis in regulating EC polarization and cerebral blood vessel assembly;
Aim 2: Determine the role of the NgBR-CCM1/2 axis in maintaining pericyte recruitment and the structural
integrity of cerebral blood vessels; Aim 3: Determine the mechanisms by which NgBR regulates CCM1/2
transcription and the contributions of NgBR-Ras pathway deficiency to the pathogenesis of sporadic CCM. The
studies proposed here will establish clear links between NgBR, CCM1/2, and cerebrovascular malformation.
Findings from our studies will provide new insight into how NgBR and NgBR-regulated factors guide CCM1/2
expression in brain ECs, and maintain the structural integrity of cerebral blood vess...

## Key facts

- **NIH application ID:** 9969458
- **Project number:** 5R01HL141733-03
- **Recipient organization:** NYU WINTHROP HOSPITAL
- **Principal Investigator:** QING MIAO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $512,759
- **Award type:** 5
- **Project period:** 2018-07-20 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9969458

## Citation

> US National Institutes of Health, RePORTER application 9969458, Roles of Nogo-B receptor in maintaining the structural integrity of blood vessels (5R01HL141733-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9969458. Licensed CC0.

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