ATF3 promotes endothelial cell response to acute lung injury
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA880905 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21595124_1.fastq.gz | Fastqsanger.gz | |||
| SRR21595124_2.fastq.gz | Fastqsanger.gz | |||
| SRR21595125_1.fastq.gz | Fastqsanger.gz | |||
| SRR21595125_2.fastq.gz | Fastqsanger.gz | |||
| SRR21595126_1.fastq.gz | Fastqsanger.gz |
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Project description:Following acute injury, the capillary vascular bed in the lung must be repaired to reestablish gas exchange between pulmonary endothelial cells (ECs) lining these vessels and the alveolar epithelium. However, the factors that control EC stress response and drive regeneration of pulmonary capillaries remain incompletely understood. Viral infections such as influenza and COVID-19 may indirectly damage lung vasculature through loss of epithelial gas exchange partners or through signaling from infiltrating immune cells. To prevent excessive tissue damage and to renew the endothelium, ECs must both withstand cellular stress and proliferate after injury. Here, we show that the transcription factor and immediate early gene Atf3 is essential for both responses in the mouse lung after influenza infection. Atf3 expression defines a subpopulation of capillary ECs enriched in genes involved in cellular response to stress, angiogenesis, and vascular development. Endothelial loss of ATF3 results in defective alveolar regeneration: in the absence of ATF3, ECs exhibit increased apoptosis and decreased proliferation, resulting in an emphysema-like phenotype with enlarged alveolar airspaces lined with regions of lost vasculature. These data implicate ATF3 as an essential component of the vascular response to acute lung injury that is required for successful lung regeneration.
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Project description:Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), cause severe endothelial dysfunction in the lung and vascular endothelial growth factor (VEGF) is elevated in ARDS. We have found that the levels of a VEGF-regulated microRNA, microRNA-1 (miR-1) is reduced in the lung endothelium after acute injury. Pulmonary endothelial cell (EC)-specific overexpression of miR-1 protects the lung against cell death and barrier dysfunction in both murine and human models and increases the survival of mice after pneumonia-induced ALI. MiR-1 has an intrinsic protective effect in pulmonary and other types of ECs; it inhibits apoptosis and necroptosis pathways and decreases capillary leak by protecting adherens and tight junctions. Comparative gene expression analysis and RISC recruitment assays identified miR-1 targets in the context of injury, including phosphodiesterase 5A (PDE5A), angiopoetin-2 (ANGPT2), connector enhancer of kinase suppressor of ras 3 (CNKSR3) and TNF alpha induced protein 2 (TNFAIP2). We validated miR-1-mediated regulation of ANGPT2 in both mouse and human ECs and found that in a 119-patient pneumonia cohort, miR-1 correlated inversely with ANGPT2. These findings illustrate the novel role of miR-1 as a cytoprotective orchestrator of endothelial response to acute injury with prognostic and therapeutic potential.
2023-10-25 | GSE236263 | GEO
Project description:Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), cause severe endothelial dysfunction in the lung and vascular endothelial growth factor (VEGF) is elevated in ARDS. We have found that the levels of a VEGF-regulated microRNA, microRNA-1 (miR-1) is reduced in the lung endothelium after acute injury. Pulmonary endothelial cell (EC)-specific overexpression of miR-1 protects the lung against cell death and barrier dysfunction in both murine and human models and increases the survival of mice after pneumonia-induced ALI. MiR-1 has an intrinsic protective effect in pulmonary and other types of ECs; it inhibits apoptosis and necroptosis pathways and decreases capillary leak by protecting adherens and tight junctions. Comparative gene expression analysis and RISC recruitment assays identified miR-1 targets in the context of injury, including phosphodiesterase 5A (PDE5A), angiopoetin-2 (ANGPT2), connector enhancer of kinase suppressor of ras 3 (CNKSR3) and TNF alpha induced protein 2 (TNFAIP2). We validated miR-1-mediated regulation of ANGPT2 in both mouse and human ECs and found that in a 119-patient pneumonia cohort, miR-1 correlated inversely with ANGPT2. These findings illustrate the novel role of miR-1 as a cytoprotective orchestrator of endothelial response to acute injury with prognostic and therapeutic potential.
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Project description:Exercise is a powerful driver of physiological angiogenesis during adulthood, but the mechanisms of exercise-induced vascular expansion are poorly understood. We explored endothelial heterogeneity in skeletal muscle and identified two capillary muscle endothelial cells (mEC) populations which are characterized by differential expression of ATF3/4. Spatial mapping showed that ATF3/4 + mECs are enriched in red oxidative muscle areas while ATF3/4 low ECs lie adjacent to white glycolytic fibers. In vitro and in vivo experiments revealed that red ATF3/4 + mECs are more angiogenic when compared to white ATF3/4 low mECs. Mechanistically, ATF3/4 in mECs control genes involved in amino acid uptake and metabolism and metabolically prime red (ATF3/4 + ) mECs for angiogenesis. As a consequence, supplementation of non-essential amino acids and overexpression of ATF4 increased proliferation of white mECs. Finally, deleting Atf4 in ECs impaired exercise-induced angiogenesis. Our findings illustrate that spatial metabolic angiodiversity determines the angiogenic potential of muscle ECs.
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