Platelet-specific TGFβ Deficiency Aggravates Atherosclerosis, Vascular Inflammation, and Hypercholesterolemia in Mice

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.The present work investigated how platelet-specific TGFβ-deficiency impacts CD4⁺ T effector cell responses and atherogenesis.Murine platelet-selective TGFβ deficiency (plt-TGFβ^-/-) was created by a <i>Pf4</i>-Cre approach, and an atherosclerotic mouse model was established by functional abrogation of <i>Ldlr</i> and 10 to 15 weeks of a high-fat diet in plt-TGFβ^-/- mice and their non-plt-TGFβ^-/- littermates.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.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.