Pericyte-derived exosomal hexokinase 2 promotes retinal neovascularization via non-metabolic ELK3 upregulation.

Retinal neovascularization (RNV) is a major cause of irreversible vision loss worldwide. Although pericyte-endothelial cell cross-talk has been implicated in RNV, the exosome-mediated mechanism underlying this interaction has remained uncharacterized. Here we found that hexokinase 2 (HK2) expression was upregulated in pericytes under hypoxic conditions both in vitro and in vivo. Hypoxic pericytes released exosomes enriched in HK2, which promoted endothelial cell growth in vitro. Conditional deletion of Hk2 in pericytes reduced neovascular tuft formation in mice with oxygen-induced retinopathy, as did inhibition of exosome release with tipifarnib. Notably, exogenous exosomal HK2 restored vascular changes caused by pericyte Hk2 deletion or tipifarnib treatment. RNA sequencing analysis revealed that exosomal HK2 upregulated the ETS transcription factor ELK3 (ELK3), whose expression was elevated in vascular tufts of mice with oxygen-induced retinopathy. Both pericyte Hk2 deletion and tipifarnib treatment suppressed ELK3 expression. Mechanistically, exosomal HK2 bound to and increased mTOR activity, leading to increased ELK3 levels. These findings identify a previously unrecognized non-metabolic role for pericyte-derived exosomal HK2 in RNV and suggest it as a potential therapeutic target.