Background: Atherosclerosis is a chronic disease of the arterial wall characterized by intimal lipoprotein retention, maladaptive inflammatory responses, and vascular remodeling processes. Smooth muscle cells (SMCs) play a crucial role in the stabilization and progression of atherosclerotic plaques by exerting 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 class I phosphatidylinositol 3'-kinase isoform α (PI3Kα) is an important signaling enzyme downstream of PDGF-mediated proliferation, survival, and migration of SMCs. The aim of our study was therefore to elucidate the unknown role of PI3Kα in SMCs during atherogenesis.
Methods and Results: SMC-specific PI3Kα-deficient Apoe-/- (Apoe-/-SMC-PI3Kα-/-) mice and Apoe-/- control animals were fed a Western-type diet for 12 weeks. SMC-specific PI3Kα ablation unexpectedly 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, SMC-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 reduced thickness of the αSMA+ fibrous cap (11,328 ± 7,864 µm² vs. 4,361 ± 3,153 µm², p < 0.05, N = 9). Even under basal conditions, SMC-specific PI3Kα ablation led to increased inflammation of the aorta, which was characterized by increased mRNA expression of the macrophage marker Cd68, the pro-atherogenic chemokine Ccl2, and the transcription factor Klf4 compared to controls.
Conclusions: The results imply that PI3Kα is a central regulator of SMC biology and counteracts vascular inflammation, atherogenesis, and plaque instability. Therefore, fine-tuning the PI3Kα signaling pathway in SMCs could represent a future therapeutic or preventive strategy.
