# Mechanisms of hypoxia induced exacerbation of cerebral cavernous malformations

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $486,230

## Abstract

Cerebral Cavernous Malformations (CCMs) are common neurovascular lesions made of endothelium clusters
filled with blood surrounded by gliosis. CCMs affect ~1/200 children and adults, causing a lifetime risk of
hemorrhagic strokes and neurologic deficits for which there is no current effective pharmacologic therapy. Loss
of function mutations in three CCM genes propels brain vascular changes. However, the propensity of CCM
lesions to form in the central nervous system (CNS) parenchyma relative to other tissues has not been fully
explained, and the heterogeneity in disease severity suggests that environmental or biological factors (e.g. other
genes, neural cells) act as disease modifiers. We and others have demonstrated that increased vascular
endothelial growth factor (VEGF) signaling and associated vascular leakage are significant contributors to CCM
disease. Our preliminary data show that hypoxic conditions contribute to an aggressive onset and progression
of CCM disease. We observed that hypoxia acts as an accelerant of CCM disease by exacerbating the number
and size of brain vascular lesions in CCM animal models. We also observed that mouse and human CCM tissue
results in increased hypoxia-inducible factor 1 alpha (HIF-1a) activity, and that proliferative astrocytes influence
CCM pathogenesis. The proposed study will test the hypothesis that hypoxia exacerbates CCMs through
hypoxic programs from astrocytes and endothelium, leading to abnormal vascular development and stroke due
to intracranial hemorrhage. Moreover, we hypothesize that intermittent hypoxia (that occurs with patients with
obstructive sleep apnea) will further exacerbate CCMs. Specific Aim 1 will test the hypothesis that hypoxia
exacerbates CCM formation by elevating hypoxia-driven genes in astrocytes in murine CCM. We will
investigate the effect of hypoxia on astrocyte gene expression (e.g., hypoxic program, VEGF) by profiling
translated mRNAs obtained from the purification of the EGFP-tagged ribosome in astrocytes in the presence or
absence of CCM lesions. Co-culture in vitro models will be used to define the interaction between CCM
endothelium and astrocytes that propels vascular dysfunction. Specific Aim 2 will test the hypothesis that
hypoxia exacerbates CCM formation by HIF-1a protein stabilization in the brain endothelium in murine
CCM. We will investigate the role of endothelial HIF-1a on changes in the endothelial barrier function, gene
expression, VEGF signaling using CCM mouse models. Specific Aim 3 will test the hypothesis that
intermittent hypoxia exacerbates murine CCM. We will investigate the role of intermittent hypoxia-driven CCM
lesion burden, using mouse models of CCM under intermittent hypoxia that partially recapitulates nocturnal
oxygen profile in patients with obstructive sleep apnea (OSA). The proposed research may lead to a new
therapeutic approach (e.g., combination therapies for activated astrocytes and CCM endothelium) and
preventive measures by defini...

## Key facts

- **NIH application ID:** 10367164
- **Project number:** 1R01NS121070-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Miguel Alejandro Lopez-Ramirez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $486,230
- **Award type:** 1
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367164

## Citation

> US National Institutes of Health, RePORTER application 10367164, Mechanisms of hypoxia induced exacerbation of cerebral cavernous malformations (1R01NS121070-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10367164. Licensed CC0.

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