Platelet-specific TGFβ deficiency aggravates atherosclerosis, vascular inflammation and hypercholesterolemia in mice

Background Atherosclerosis involves inflammatory and thrombotic mechanisms, to which platelets, CD4 ⁺ T effector cells, and transforming growth factor β (TGFβ) all contribute importantly. Platelets are the principal source of circulating TGFβ, which profoundly regulates CD4 ⁺ T effector cell responses. The impact of platelet-derived TGFβ on atherosclerosis is, however, unknown. Objectives The present work investigated how platelet-specific TGFβ-deficiency impacts CD4 ⁺ T effector cell responses and atherogenesis. Methods Murine platelet-selective TGFβ-deficiency (plt-TGFβ ^−/− ) was created by a Pf4 -Cre approach, and an atherosclerotic mouse model was established by functional abrogation of Ldlr and 10–15 weeks of a high-fat diet in plt-TGFβ ^−/− mice and their non-plt-TGFβ ^−/− littermates. Results En face Oil Red O staining of the aorta showed more atherosclerotic lesion formation in plt-TGFβ ^−/− mice, with significant increases in both lesion size and lesion coverage of the total aortic area. Cryosections of the aortic root confirmed the aggravation of atherogenesis. Platelet-derived TGFβ deficiency increased circulating platelets and plasma levels of total cholesterol, LDL-cholesterol, and triglycerides after a 10 or 15 week high-fat diet period. RNA sequencing and proteomic analyses of the aorta showed signs of CD4 ⁺ T effector cell and macrophage activation in plt-TGFβ ^−/− mice. Conclusions Platelet-specific TGFβ deficiency aggravates atherosclerosis, via increasing arterial inflammation and plasma levels of cholesterol. Our findings demonstrate that platelet-derived TGFβ is prominently athero-protective.