Inhibition of transforming growth factor-beta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice

Atherosclerosis is a disease of the arterial wall that seems to be tightly modulated by the local inflammatory balance. Whereas a large body of eviden ce supports a role for proinflammatory mediators in disease progression, th e understanding of the role of the antiinflammatory component in the modula tion of plaque progression is only at its beginning. TGF-beta1, -beta2, and -beta3 are cytokines/growth factors with broad activities on cells and tis sues in the cardiovascular system and have been proposed to play a role in the pathogenesis of atherosclerosis. However, no study has examined the dir ect role of TGF-beta in the development and composition of advanced atheros clerotic lesions. In the present study, we show that inhibition of TGF-beta signaling using a neutralizing anti-TGF-beta1, beta2, and -beta3 antibody accelerates the development of atherosclerotic lesions in apoE-deficient mi ce. Moreover, inhibition of TGF-beta signaling favors the development of le sions with increased inflammatory component and decreased collagen content. These results identify a major protective role for TGF-beta in atheroscler osis.