P1937Deficiency of PI 3-kinase isoform p110alpha in smooth muscle cells impairs vascular integrity and promotes aortic aneurysm formation

Abstract

Abstract Background The pathobiology of aortic aneurysms is characterized by vascular inflammation, extracellular matrix degeneration, and particularly by loss and dedifferentiation of vascular smooth muscle cells (SMCs). In SMCs, the PI 3-kinase isoform p110α mediates receptor tyrosine kinase dependent proliferation, chemotaxis, and survival. Smooth muscle specific p110α deficient mice (SM-p110α−/− mice) display reduced medial wall thickness, substantially reduced neointima formation and media hypertrophy after balloon injury of the carotid artery. Objective We hypothesized that loss of p110α signaling impairs vascular integrity and promotes development and progression of abdominal aortic aneurysms (AAA). We aimed to elucidate the impact of p110α deficiency on vascular integrity, SMC phenotypic modulation, vascular inflammation, and AAA formation. Methods and results Ultra-structural characterization of aortic wall morphology in abdominal aortas from SM-p110α−/− mice by transmission electron microscopy (TEM) revealed disarranged structure of tunica media as indicated by disorganized elastic fibers, detached SMCs, and elastic fiber breaks. Western blots showed reduced elastin and fibrillin expression in SMCs from p110α−/− mice. Media thickness was significantly reduced in abdominal aortas from SM-p110α−/− mice compared to wild type (WT) controls (29.0±3.1 vs. 42.5±4.1 μm). Lack of p110α decreased expression of differentiation markers SM-α-actin and SM-MHC. p110α deficiency significantly diminished responsiveness of aortic rings to vasodilator acetylcholine. These data indicate loss of differentiation and impaired contractility of p110α−/− SMCs. We subjected SM-p110α−/− mice and WT littermate controls to the porcine pancreatic elastase (PPE) model of AAA. PPE was infused into the infrarenal aorta, respectively, to induce AAA formation. Ultrasonic examination of abdominal aortas demonstrated an enlarged aortic diameter in PPE challenged mice. AAA formation was significantly (p<0.01) enhanced in SM-p110α−/− (0.46±0.12 mm, n=8) compared to SM-p110α+/+ mice (0.18±0.03 mm, n=4). These data indicate a protective function of p110α in AAA formation. Immunocytochemistry of the aortic medial compartment from PPE-perfused SM-p110α−/− mice revealed significantly increased MOMA-2+ monocyte/macrophage content indicating augmented aortic inflammation during AAA formation compared to WT controls. Furthermore, SMCs from SM-p110α−/− mice expressed reduced amounts of anti-inflammatory angiopoietin1 compared to p110α+/+ SMCs. Moreover, frequent apoptotic/necrotic SMCs were found in the aortic media of SM-p110α−/− mice by TEM, potentially contributing to vascular inflammation in a critical fashion. Conclusion These data indicate that p110α signaling critically contributes to vascular integrity via maintaining SMC plasticity, elastic fiber homeostasis, and anti-inflammatory processes. Consequently, lack of proper p110α signaling promotes progression of AAA formation.