PI3 kinase-α protects against vascular inflammation, atherosclerosis, and plaque instability by regulating the biology of vascular smooth muscle cells

Background Atherosclerosis is a chronic disease of the arterial wall characterized by intimal lipoprotein retention, maladaptive inflammatory responses, and vascular remodeling processes. Vascular smooth muscle cells (VSMCs) play a crucial role in the stabilization and progression of atherosclerotic plaques by performing both atheroprotective and pro-atherogenic functions. Recent studies suggest an important role for pleiotropic growth factors such as platelet-derived growth factor (PDGF) in the regulation of these processes. Previous studies from our laboratory have shown that the class I phosphatidylinositol 3'-kinase isoform α (PI3Kα) is an important signaling enzyme downstream of PDGF-mediated proliferation, survival, and migration of VSMCs. Purpose The aim of our study was therefore to elucidate the unknown role of PI3Kα in VSMCs during atherogenesis. Methods and Results VSMC-specific PI3Kα-deficient Apoe-/- (Apoe-/-SMC-PI3Kα-/-) mice and Apoe-/- control animals were fed a Western-type diet for 12 weeks or kept on a chow diet. Even under basal conditions, VSMC-specific PI3Kα ablation led to increased inflammation of the aorta, which was characterized by increased mRNA expression of the myeloid cell integrin Cd11b as well as proatherogenic adhesion molecules, cytokines, and chemokines such as Vcam1, Icam1, Sele, Selp, Tnf, Il12, Ccl2, Cxcl12, and the matrix metalloproteinase Mmp2 compared to controls. Consequently, PI3Kα ablation in VSMCs led to a significant increase in atherosclerotic lesions throughout the aorta of Apoe-/-SMC-PI3Kα-/- mice compared to Apoe-/- controls (6.0 ± 2.1% vs. 3.3 ± 1.2%, p < 0.0001, N = 21–23). Similarly, atherosclerotic lesions at the level of the aortic roots were enlarged in Apoe-/-SMC-PI3Kα-/- mice (8.8 ± 3.8% vs. 6.4 ± 3.3%, p < 0.05, N = 17–19), although these mice had similar body weight and serum lipid levels to Apoe-/- controls. Further analyses revealed that the relative plaque content of Mac-2+ macrophages in Apoe-/-SMC-PI3Kα-/- mice was similar to that in Apoe-/- controls despite increased atherosclerosis. However, VSMC-specific PI3Kα deficiency resulted in decreased indices of plaque stability such as reduced collagen content (11.0 ± 5.9% vs. 29.5 ± 15.7%, p < 0.0001, N = 17–18) and αSMA content (12.5 ± 4.9% vs. 7.0 ± 3.7%, p < 0.001, N = 13-15) as well as reduced thickness of the αSMA+ fibrous cap (11,328 ± 7,864 µm² vs. 4,361 ± 3,153 µm², p < 0.05, N = 9). Conclusions Our results show that PI3Kα is a central regulator of VSMC biology and counteracts vascular inflammation, atherosclerosis, and plaque instability. Therefore, fine-tuning the PI3Kα signaling pathway in VSMCs could represent a future therapeutic or preventive strategy.