ANRIL modulates endothelial senescence and angiogenesis through SASP-driven miR146a regulation in age-related vascular dysfunction

Vascular aging, marked by endothelial cell (EC) dysfunction and compromised angiogenesis, is a central driver of age-related ischemic diseases. Although lncRNAs have emerged as pivotal regulators of endothelial function, their specific roles in endothelial aging remain enigmatic. In this study, we identify the lncRNA ANRIL as a crucial modulator of endothelial dysfunction during aging. By analyzing publicly available lncRNA sequencing datasets comparing young and old ECs, we pinpointed ANRIL and validated its role through a replicative senescence model in human umbilical vein ECs (HUVECs) and FACS sorting of skeletal muscle ECs from aged mice. While ANRIL showed minimal direct effects on angiogenesis, functional assays and transcriptomic analysis revealed its profound impact on the senescence-associated secretory phenotype (SASP). Remarkably, ANRIL regulates the expression of miR146a in ECs, which is transferred to macrophages, where it inhibits VEGF secretion and disrupts endothelial neovascularization. In vivo, ANRIL downregulation in a murine hindlimb ischemia model significantly enhanced neovascularization and restored blood flow, revealing its therapeutic potential for ischemic diseases. These findings position ANRIL as a novel, potent regulator of endothelial senescence, offering new insights into the molecular basis of vascular aging and suggesting ANRIL as a promising therapeutic target to mitigate age-related vascular dysfunction.