Early IKKb-dependent anabolic and fibrotic signature governs vascular smooth muscle cells fate and abdominal aortic aneurysm development

Abdominal aortic aneurysm (AAA) is a serious disease with no effective pharmacological therapy. Although inflammation is recognized as a key regulator of AAA, targeting inflammatory pathways once the disease is established does not improve outcomes. Understanding the earliest molecular indicators could clarify precise biological targets and prognostic markers for AAA. Using ApoE-deficient mice, we performed RNA-Seq on suprarenal abdominal aortas (SRAs) from Ang II- and saline-treated mice 24 h after infusion. We further developed a unique model of hyperlipidemic mice in which the expression of the inhibitor of nuclear factor kappa B kinase subunit beta (IKKβ) can be conditionally suppressed in vascular smooth muscle cells (VSMCs). RNA-Seq data revealed early IKKβ-dependent cellular anabolic processes in SRAs, including activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, deletion of the Ikbkb gene in VSMCs significantly reduced the rate of aneurysm rupture in mice exposed to Ang II. In situ analysis further confirmed that the absence of IKKβ in VSMCs is associated with a reduced inflammatory response and the preservation of their contractile phenotypes. Our results reinforce the crucial role of VSMCs in rapid adaptation, leading to deleterious inflammation-dependent remodeling of the vascular wall, and define a previously unrecognized anabolic role of IKKβ in AAA pathogenesis.