Dietary fat and reduced levels of TGF beta 1 act synergistically to promote activation of the vascular endothelium and formation of lipid lesions

Transforming growth factor-beta (TGF beta) has a wide range of activities o n vascular cells and inflammatory cells, suggesting it may have different f unctions during various stages of atherogenesis. We report that mice hetero zygous for the deletion of the fgfb1 gene (tgfb1(+/-) mice) have reduced le vels of TCF beta 1 in the artery wall until at least 8 weeks of age. On a n ormal mouse chow diet, the vascular endothelium of tgfbv1(+/-) mice is indi stinguishable from wild-type littermates, assessed by morphology and interc ellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecu le-1 (VCAM-1) expression, In contrast, levels of the smooth muscle isoforms of actin and myosin in medial smooth muscle cells of tg;tgfb1(+/-) mice ar e significantly reduced, Following feeding a cholesterol-enriched diet for 12 weeks, high levels of ICAM-1 and VCAM-1 were detected in the vascular en dothelial cells of tgfb1(+/-) mice, but not wild-type mice, Furthermore, ma rked deposition of lipid into the artery wall was only observed in the tafb 1(+/-) mice on the cholesterol-enriched diet, These vascular lipid lesions were accompanied by local invasion of macrophages. We conclude that deletio n of a single allele of the tgfb1 gene results in a reduced level of TGF be ta 1 antigen in the aorta together with reduced smooth muscle cell differen tiation, whereas the addition of a high fat dietary challenge is required t o activate the vascular endothelium and to promote the formation of fatty s treaks resembling early atherosclerosis in humans.