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Vascular endothelium, the inner most lining of all blood vessels, controls the transport of nutrients, protein, water, and leukocytes across the vessel wall and thereby maintains lung tissue and fluid homeostasis. Damage to endothelial integrity caused by mediagenic, inflammatory, or toxic agents results in pulmonary edema, inflammation, organ failure, and high lethality. A key pathogenic characteristic of vascular injury involves an excessive loss of endothelial cells (EC) accompanied by the generation of inflammatory cytokines. Genome-wide analyses of DNA methylation, the most enduring epigenetic modification of DNA, and its impact on EC transcriptomes and cellular functions, still lack comprehensive understanding. We demonstrate that lipopolysaccharide (LPS) elevated DNA methylation in EC within the lungs, primarily through a mechanism dependent on DNA methyltransferase 3a (DNMT 3a). Mice with endothelial cell-specific deletion of DNMT3a ( EC-DNMT3a −/− ) promptly recovered from lung injury, attributed to a reduction of EC death. Furthermore, we observed that the deletion of DNMT3a in EC led to an increase in the expression of the apoptosis inhibitor B-cell lymphoma 2 (BCL2). Collectively, the data implies that inhibiting DNMT3a activity plays a crucial role in reshaping the EC methylome and promoting BCL-2 activity. This, in turn, facilitates the generation of reparative EC and contributes to the resolution of acute lung injury (ALI). These findings offer insights into potential targets for preventing ALI. American Heart Association (AHA) Postdoctoral Fellowship (19POST34450241). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Akhter et al. (Wed,) studied this question.