Abstract Background Catalytic class IA PI 3-kinase isoform p110α is a crucial regulator of cellular proliferation and survival in numerous cell types. While p110α is critically involved in pathogenic vascular remodeling, its physiological role for vascular integrity under stress conditions has not been studied. We report a protective function of smooth muscle p110α against abdominal aortic aneurysm (AAA) formation. Methods &amp; Results In mice lacking p110α in smooth muscle cells (sm-p110α -/- ), perfusion of the infrarenal aorta with porcine pancreatic elastase (PPE) yielded substantially enhanced AAA formation compared to wild type controls. This disease phenotype is partly attributable to a subtle preexisting vascular phenotype under basal conditions, as sm-p110α -/- mice displayed a smaller media area, deranged aortic wall structure (detached smooth muscle cells, increased apoptotic cell death), and a diminished functional responsiveness of aortic rings to vasodilators. Furthermore, p110α is also implicated in regenerative processes during AAA development: Whereas wild type mice showed increased media hypertrophy, neointima formation and proliferation upon PPE intervention, these vascular remodeling processes were diminished in sm-p110α -/- mice. Concomitantly, increased numbers of elastic fiber breaks and ECM degradation were detected in sm-p110α -/- aorta. Mechanistically, we found that lack of p110α expression impaired smooth muscle cell proliferation, expression of contractile marker genes and production of elastin fibers. This phenotype largely depended on reduced phosphorylation and inactivation of FOXO1, as specific FOXO1 inhibition fully rescued proliferation of p110α -/- smooth muscle cells, and knockdown of FOXO1 increased expression of calponin and elastin. Conclusions Smooth muscle p110α protects against AAA disease by maintaining aortic wall homoeostasis and promoting SMC proliferation to compensate for cell loss during AAA development. Our findings have potential implications for current approaches aimed at p110α inhibition for cancer therapy and suggest new pharmacological strategies to activate p110α signaling in AAA disease.

PI 3-kinase isoform p110α controls smooth muscle cell functionality and protects against aortic aneurysm formation