PI 3-kinase isoform p110α mediated FOXO1 inactivation protects against aortic aneurysm formation

p110α signaling in smooth muscle cells protects mice from porcine pancreatic elastase–induced abdominal aortic aneurysm by maintaining SMC proliferation, reparative phenotype, and elastin integrity.

• Why it matters: AAA progression involves loss of contractile SMCs and impaired vascular remodeling, so therapies that preserve or regenerate aortic SMC content are needed.
• What they did: Mice with SMC-specific p110 loss (sm-p110-/-) or FOXO1 loss (sm-FOXO1-/-) were tested in the PPE AAA model using ultrasound, histology, electron microscopy, functional assays, and scRNA-seq in tamoxifen-inducible ism-p110-/--eYFP lineage tracing mice.
• The result: p110 deficiency aggravated AAA with reduced SMC content and proliferation, increased elastic fiber breaks and ECM degradation, and scRNA-seq showed fewer proliferative/reparative SMC clusters plus more inflamed SMCs; FOXO1 inactivation rescued the p110-deficient phenotype and protected against AAA, while p110 activation ameliorated AAA in wild type but not sm-FOXO1-/- mice.