MIAT-DHX9 spatiotemporal expression drives venous neointimal hyperplasia through nucleolar homeostasis and mitotic progression.
Venous neointimal hyperplasia, characterized by the abnormal proliferation of smooth muscle cells (SMCs), represents a critical contributor to vascular stenosis and therapeutic failure in vascular interventions. Here, we identified a novel role of spatiotemporal nucleolar expression of DExH-box helicase 9 (DHX9) and its binding partner, the long non-coding RNA (lncRNA) MIAT in venous neointimal pathogenesis. In normal SMCs, DHX9 transiently localized to nucleoli during the early S phase. Pathologically, endogenous-activated MIAT facilitated nucleolar DHX9 location and its interaction with PARP1. Activated-MIAT induced mitotic spindle pole location of DHX9 which was destroyed by PARP inhibitor. MIAT also drove SMCs proliferation by accelerating cell cycle progression. While depleting MIAT or DHX9 led to remarkable nucleolar subphase disruption, mitotic breakage-fusion-bridge, and DNA damage. Of note, nucleolar-associated morphology phenotypes analyzed with deep learning are determined to be valuable biomarkers for assessing cellular status and disease progress. MIAT was repressed in cultured human veins, reducing SMCs proliferation and vascular intimal hyperplasia. These results establish the MIAT-DHX9 axis as the central regulator of venous SMCs in arteriovenous fistula and venous graft models. Our study may provide a new avenue to destroy the pathologic spatiotemporal function of DHX9 by targeting MIAT in intimal hyperplasia. Overall design: RNA-seq data for rat VSMCs with lncRNA MIAT knockdown treatment for 72 hours, n = 3 each group.