Atypical p38 Kinase Signaling in Retinal Vascular Damage and Recovery

ABSTRACT Despite the life‐changing impact of anti‐VEGF therapies, vascular retinopathies continue to affect millions of patients worldwide. To better understand disease progression, it is essential to define alternative mechanisms that contribute to retinal vascular dysregulation. Mitogen‐activated protein kinase (MAPK) p38 plays a significant role in regulating vascular homeostasis, angiogenesis, and retinal disease progression, yet effective therapeutic targeting remains elusive. An alternative atypical p38 signaling pathway is mediated by interaction with the adaptor protein TGF‐beta activated kinase 1, binding protein 1 (TAB1). Atypical p38 can be activated by ischemia or by inflammatory G protein‐coupled receptors (GPCRs) to regulate inflammation and vascular homeostasis. However, atypical signaling has not been investigated in the context of vascular retinopathies, specifically oxygen‐induced retinopathy (OIR). Here, we utilized a genetic knock‐in mouse to block atypical p38 activity (Tab1 KI ) to explore retinal damage during OIR. We report that Tab1 KI mice display significantly reduced vaso‐obliteration and limited neovascularization relative to wild‐type C57BL6 controls. Retinal RNAseq analysis revealed distinct transcriptional regulation in the Tab1 KI mouse. Suppression of atypical p38 reduced Mef2c signaling, which in turn enhanced microglial activation and inflammation. Despite the upregulation of proangiogenic markers, the increase in endothelial markers does not correlate with the dysregulated growth of blood vessels. Instead, Mef2c suppression reduces pathological angiogenesis while increasing physiological vascular regrowth. The combined data suggest that the selective inhibition of atypical p38 signaling could block the enhanced pathogenic neovascular tuft formation without impacting blood vessel repair. Further investigation will clarify how atypical p38 controls neovascular responses, potentially revealing new treatment strategies for vascular retinopathies.