Cardiac Endothelial Enhancer RNA Tek‐e1 Restores Microvascular Homeostasis After Myocardial Infarction

Microvascular repair after myocardial infarction involves both angiogenesis and re-establishment of vascular homeostasis. Here, we identify a distinct transcriptionally active state in hypoxic border-zone endothelial cells driven by KDM5A downregulation and biased towards endothelial stabilization and microvascular homeostatic repair. KDM5A loss increases H3K4me3 enrichment at the Tek promoter and an intronic enhancer, enabling ISL1 to coordinately activate transcription of Tek and the enhancer RNA Tek-e1. Tek-e1 acts as an essential cis-regulatory RNA that further amplifies Tek/TIE2 expression through R-loop formation and reinforced enhancer-promoter communication, thereby converting Kdm5a-loss-induced epigenetic activation into persistent transcriptional reinforcement. In mice with endothelial-specific deletion of Kdm5a, this mechanism promotes the maturation and stabilization of nascent-microvascular networks after myocardial infarction. In a clinical cohort, serum soluble TIE2 independently stratified collateral status in 402 patients with chronic total occlusion. To further enable translation, we developed LNP@Tek-e1 modified with a VCAM-1-targeting peptide, combining VCAM-1-directed endothelial enrichment with enhancer-dependent Tek-e1 activity to selectively enhance Tek/TIE2 expression in border-zone endothelium, improving microvascular function and limiting adverse left ventricular remodelling. Together, these findings define KDM5A downregulation as a hypoxia-triggered endothelial repair programme and establish Tek-e1 as an essential cis-regulatory amplifier that can be delivered in vivo to restore post-infarction microvascular homeostasis.