Angiogenic gene networks are dysregulated in opioid use disorder: evidence from multi-omics and imaging of postmortem
Emily F Mendez1, Haichao Wei2,3, Ruifeng Hu4
1Louis A. Faillace, MD, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.
Abstract:
Opioid use disorder (OUD) is a public health crisis in the U.S. that causes over 50 thousand deaths annually due to overdose. Using next-generation RNA sequencing and proteomics techniques, we identified 394 differentially expressed (DE) coding and long noncoding (lnc) RNAs as well as 213 DE proteins in Brodmann Area 9 of OUD subjects. The RNA and protein changes converged on pro-angiogenic gene networks and cytokine signaling pathways. Four genes (LGALS3, SLC2A1, PCLD1, and VAMP1) were dysregulated in both RNA and protein. Dissecting these DE genes and networks, we found cell type-specific effects with enrichment in astrocyte, endothelial, and microglia correlated genes. Weighted-genome correlation network analysis (WGCNA) revealed cell-type correlated networks including an astrocytic/endothelial/microglia network involved in angiogenic cytokine signaling as well as a neuronal network involved in synaptic vesicle formation. In addition, using ex vivo magnetic resonance imaging, we identified increased vascularization in postmortem brains from a subset of subjects with OUD. This is the first study integrating dysregulation of angiogenic gene networks in OUD with qualitative imaging evidence of hypervascularization in postmortem brain. Understanding the neurovascular effects of OUD is critical in this time of widespread opioid use.
Insights
Opioid use disorder (OUD) alters brain gene networks, increasing blood vessel growth. This study reveals new neurovascular targets for treating OUD, a major public health crisis.
Area of Science:
- Neuroscience
- Genomics
- Proteomics
Background:
- Opioid use disorder (OUD) is a significant public health issue causing numerous overdose deaths annually.
- Brain region Brodmann Area 9 is implicated in OUD pathophysiology.
Purpose of the Study:
- To investigate the molecular and neurovascular changes in the brain associated with OUD.
- To identify specific genes, pathways, and cellular mechanisms affected by OUD.
Main Methods:
- Utilized next-generation RNA sequencing and proteomics to analyze postmortem brain tissue from OUD subjects.
- Employed Weighted-genome correlation network analysis (WGCNA) to identify cell-type specific gene networks.
- Conducted ex vivo magnetic resonance imaging (MRI) to assess brain vascularization.
Main Results:
- Identified 394 differentially expressed RNAs and 213 differentially expressed proteins in Brodmann Area 9.
- Observed convergence of molecular changes on pro-angiogenic gene networks and cytokine signaling pathways.
- Found evidence of increased vascularization in postmortem brains of OUD subjects, linked to astrocyte, endothelial, and microglia pathways.
Conclusions:
- This study provides the first integrated molecular and imaging evidence of angiogenic gene network dysregulation and hypervascularization in the OUD brain.
- Findings highlight the critical role of neurovascular alterations in OUD.
- Identified potential therapeutic targets within angiogenic and cytokine signaling pathways for OUD treatment.
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