Platelet-specific TGFβ1 deficiency aggravates atherosclerosis, vascular inflammation, and hypercholesterolemia in mice

Atherosclerosis involves inflammatory and thrombotic mechanisms, to which both platelets and transforming growth factor {beta} (TGF{beta}) contribute. The effect of platelet-derived TGF{beta} on atherosclerosis is, however, unknown and therefore investigated. Murine platelet-selective TGF{beta}-deficiency (plt-TGF{beta}-/-) 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-TGF{beta}-/- mice and their non-plt-TGF{beta}-/- littermates. En face Oil Red O staining of the aorta showed more atherosclerotic lesion formation in plt-TGF{beta}-/- 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 TGF{beta} 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-TGF{beta}-/- mice. In conclusion, platelet-specific TGF{beta} deficiency aggravates atherosclerosis, via increasing arterial inflammation and plasma levels of cholesterol. Our findings demonstrate that platelet-derived TGF{beta} is prominently athero-protective. Key pointsO_LIPlatelet-specific transforming growth factor {beta} (TGF{beta}) deficiency markedly enhances atherosclerosis in a high-fat diet-fed murine model. C_LIO_LIPlatelet TGF{beta} deficiency aggravates hyperlipidemia, with further elevations of total cholesterol, LDL-cholesterol, and triglycerides. C_LI