Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a cr...

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Bibliographic Details
Published in:The Journal of clinical investigation 2021-07, Vol.131 (13)
Main Authors: Lopez-Ramirez, Miguel Alejandro, Lai, Catherine Chinhchu, Soliman, Shady Ibrahim, Hale, Preston, Pham, Angela, Estrada, Esau J, McCurdy, Sara, Girard, Romuald, Verma, Riya, Moore, Thomas, Lightle, Rhonda, Hobson, Nicholas, Shenkar, Robert, Poulsen, Orit, Haddad, Gabriel G, Daneman, Richard, Gongol, Brendan, Sun, Hao, Lagarrigue, Frederic, Awad, Issam A, Ginsberg, Mark H
Format: Article
Language:English
Subjects:
Animals
Apoptosis Regulatory Proteins - deficiency
Apoptosis Regulatory Proteins - genetics
Astrocytes
Astrocytes - pathology
Astrocytes - physiology
Cerebrovascular disease
Complications and side effects
Cyclooxygenase 2 - genetics
Cyclooxygenase 2 - metabolism
Development and progression
Disease Models, Animal
Disease Progression
Endothelial Cells - metabolism
Genetic aspects
Health aspects
Hemangioma, Cavernous, Central Nervous System - etiology
Hemangioma, Cavernous, Central Nervous System - pathology
Hemangioma, Cavernous, Central Nervous System - physiopathology
Human Umbilical Vein Endothelial Cells
Humans
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Kruppel-Like Factor 4
Kruppel-Like Transcription Factors - genetics
Kruppel-Like Transcription Factors - metabolism
Life Sciences
Mice
Mice, Knockout
Models, Neurological
Mutation
Neurovascular diseases
Nitric Oxide - biosynthesis
Nitric Oxide Synthase Type III - genetics
Nitric Oxide Synthase Type III - metabolism
RNA, Messenger - genetics
RNA, Messenger - metabolism
Vascular Endothelial Growth Factor A - biosynthesis
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Summary:Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2- and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1α in astrocytes, resulting in increased VEGF production and expression of a "hypoxic" program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1α target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.
ISSN:1558-8238
0021-9738
1558-8238
DOI:10.1172/JCI139570