RNA Splicing of the REST Gene by SRRM4 in Vascular Smooth Muscle Cells Promotes Abdominal Aortic Aneurysm Development

Background: Abdominal aortic aneurysm (AAA) progression is closely associated with the phenotypic switch of vascular smooth muscle cells (VSMCs). Although members of the serine/arginine-rich splicing factor (SR) superfamily are increasingly recognized for modulating cell phenotype, their specific contribution to AAA development has remained underexplored.

Methods: The researchers integrated whole-transcriptome analyses of human and murine AAA tissues from clinical samples and animal models and identified serine-arginine repeat matrix 4 (SRRM4) as a candidate gene regulating AAA formation. To investigate its role, they used global and VSMC-specific SRRM4-knockout mice to construct AAA models in two different ways, and further studied SRRM4's impact in in vivo and in vitro models.

Results: Elevated SRRM4 mRNA and protein levels were observed in VSMCs from both human and murine AAA tissues. Targeted silencing of SRRM4 in VSMCs, but not in endothelial or myeloid cells, significantly attenuated AAA formation in both AngII- and CaCl2-induced mouse models. The study identifies RE1 silencing transcription factor (REST), a master regulator of cellular phenotypic stability, as a critical target gene of SRRM4 in AAA. SRRM4 modulates VSMC phenotype through alternative splicing of the REST gene, producing a non-functional REST4 isoform. It further shows that REST directly represses STAT1, a mechanism by which SRRM4 influences VSMC phenotypic transition. Clinically, inhibiting both STAT1 expression and function was beneficial for preventing AAA formation and slowing disease progression in mouse models.

Conclusions: The investigation uncovers a previously unrecognized role of SRRM4-mediated splicing of the REST gene in AAA progression and identifies a novel REST/STAT1 axis critical for VSMC phenotypic modulation. These findings may provide insights for developing innovative therapeutic strategies for AAA.