Hypoxia-induced endothelial exosomal MSTRG.12883.2 enhances ox-LDL- induced phenotypic switching of vascular smooth muscle cells.

AIMS: Plaque regions in atherosclerosis (AS) exhibit sustained moderate hypoxia, which may impair endothelial function and influence vascular smooth muscle cell (VSMC) behavior. This study aims to investigate hypoxia-responsive endothelial-derived long noncoding RNAs (lncRNAs), and their role in enhancing oxidized low-density lipoprotein(ox-LDL)-induced phenotypic switching of VSMCs. MATERIALS AND METHODS: Differentially expressed lncRNAs in endothelial cells (ECs) under hypoxia were selected for analysis and validated by qRT-PCR. Luciferase and ChIP-PCR assays were performed to assess HIF-2α-mediated transcriptional regulation of MSTRG.12883.2. Bioinformatic analysis, luciferase and RIP assays were conducted to examine the interaction between MSTRG.12883.2 and the miR-632/KLF4 axis. Exosomes were isolated and characterized, and exosome-dependent transfer of MSTRG.12883.2 from ECs to VSMCs was demonstrated. Phenotypic switching of VSMCs was evaluated using functional assays (CCK-8 and migration assays) and molecular analyses (ELISA and Western blotting). KEY FINDINGS: MSTRG.12883.2 was identified as a hypoxia-induced, endothelial-enriched lncRNA transcriptionally regulated by HIF-2α. Preferentially enriched in exosomes, it is transferred from ECs to VSMCs. Mechanistically, MSTRG.12883.2 acts as a competing endogenous RNA that sponges miR-632, thereby relieving KLF4 repression and facilitating the ox-LDL-induced transition of VSMCs from a contractile to a synthetic phenotype. SIGNIFICANCE: We reveal that the unique plaque microenvironment triggers the expression of endothelial-derived MSTRG.12883.2, leading to its exosomal transfer to VSMCs. This hypoxia-responsive axis serves as a key driver of plaque destabilization and vascular remodeling. Together, these findings highlight a critical layer of endothelial-VSMC communication in AS and position MSTRG.12883.2 as a potent diagnostic and therapeutic target.