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Aberrant regulation of retinoic acid signaling genes in cerebral arterio venous malformation nidus and neighboring astrocytes

Authors
  • Thomas, Jaya Mary1, 2
  • Sasankan, Dhakshmi1
  • Surendran, Sumi1
  • Abraham, Mathew3
  • Rajavelu, Arumugam1
  • Kartha, Chandrasekharan C.1, 4
  • 1 Rajiv Gandhi Centre for Biotechnology, Poojapura, Thycaud, Thiruvananthapuram, Kerala, 695014, India , Thiruvananthapuram (India)
  • 2 Manipal Academy of Higher Education, Madhav Nagar, Manipal, Karnataka, 576104, India , Manipal (India)
  • 3 Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, 695011, India , Thiruvananthapuram (India)
  • 4 Kerala Institute of Medical Sciences, Thiruvananthapuram, Kerala, 695029, India , Thiruvananthapuram (India)
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Mar 01, 2021
Volume
18
Issue
1
Identifiers
DOI: 10.1186/s12974-021-02094-2
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundCerebral arterio venous malformations (AVM) are a major causal factor for intracranial hemorrhage, which result in permanent disability or death. The molecular mechanisms of AVM are complex, and their pathogenesis remains an enigma. Current research on cerebral AVM is focused on characterizing the molecular features of AVM nidus to elucidate the aberrant signaling pathways. The initial stimuli that lead to the development of AVM nidus structures between a dilated artery and a vein are however not known.MethodsIn order to understand the molecular basis of development of cerebral AVM, we used in-depth RNA sequencing with the total RNA isolated from cerebral AVM nidus. Immunoblot and qRT-PCR assays were used to study the differential gene expression in AVM nidus, and immunofluorescence staining was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues. Immunohistochemistry was used to study the expression pattern of aberrant proteins in AVM nidus and control tissues.ResultsThe transcriptome study has identified 38 differentially expressed genes in cerebral AVM nidus, of which 35 genes were upregulated and 3 genes were downregulated. A final modular analysis identified an upregulation of ALDH1A2, a key rate-limiting enzyme of retinoic acid signaling pathway. Further analysis revealed that CYR61, a regulator of angiogenesis, and the target gene for retinoic acid signaling is upregulated in AVM nidus. We observed that astrocytes associated with AVM nidus are abnormal with increased expression of GFAP and Vimentin. Triple immunofluorescence staining of the AVM nidus revealed that CYR61 was also overexpressed in the abnormal astrocytes associated with AVM tissue.ConclusionUsing high-throughput RNA sequencing analysis and immunostaining, we report deregulated expression of retinoic acid signaling genes in AVM nidus and its associated astrocytes and speculate that this might trigger the abnormal angiogenesis and the development of cerebral AVM in humans.

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