Angiogenic gene networks are dysregulated in opioid use disorder: evidence from multi-omics and imaging of postmortem human brain

• Published in: Molecular psychiatry Vol. 26; no. 12; pp. 7803 - 7812
• Main Authors: Mendez, Emily F., Wei, Haichao, Hu, Ruifeng, Stertz, Laura, Fries, Gabriel R., Wu, Xizi, Najera, Katherine E., Monterey, Michael D., Lincoln, Christie M., Kim, Joo-won, Moriel, Karla, Meyer, Thomas D., Selvaraj, Sudhakar, Teixeira, Antonio L., Zhao, Zhongming, Xu, Junqian, Wu, Jiaqian, Walss-Bass, Consuelo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2021; Nature Publishing Group
• Subjects: 38; 38/91; 59/57; 631/208; 631/337; 692/53; 82; 82/58; Angiogenesis; Autopsy; Behavioral Sciences; Biological Psychology; Brain - diagnostic imaging; Brain - metabolism; Brodmann's area; Cytokines; Drug addiction; Drug Overdose; Gene Regulatory Networks - genetics; Genes; Genetic aspects; Genomes; Health aspects; High-Throughput Nucleotide Sequencing; Humans; Identification and classification; Magnetic resonance imaging; Medicine; Medicine & Public Health; Microglia; Narcotics; Neovascularization; Neovascularization, Pathologic; Neuroimaging; Neurosciences; Non-coding RNA; Opioid-Related Disorders - genetics; Opioids; Overdose; Pharmacotherapy; Proteomics; Psychiatry; Public health; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; Signal Transduction; Substance use disorder; Vascularization; United States
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-021-01259-y

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.