The transforming growth factor type-β (TGF-β) family plays a major role in the repair of injured blood vessel walls and induces a wide range of responses in vascular smooth muscle cells (VSMCs). One very important function of TGF-β is its antiproliferative effect. Normal VSMCs generally exhibit reduced proliferation in response to TGF-β stimuli, while lesion-derived VSMCs (LDCs) show a selective resistance to the antiproliferative effect of TGF-β, as seen in atherosclerosis. The overall goal of this dissertation was to examine the mechanisms and factors that contribute to smooth muscle cells resistance to TGF-β signaling in atherosclerosis.

Among different causes of resistance, there were identified several molecular mechanisms that may be responsible for the TGF-β-induced antiproliferative response. Primarily, lesion-derived VSMC have a low level of Smad3 protein due to its rapid degradation by the ubiquitin-proteasomal machinery. Moreover, blocking the degradation of Smad3 is capable of restoring the adequate level of detectable endogenous Smad3 protein, but does not affect significantly the antiproliferative response, suggesting that non-degraded Smad3 may be sequestered in the cytoplasm and the translocation to the nucleus of phosphorylated protein is impeded. Overall, the general conclusion of this thesis is that an adequate level of Smad3 is necessary for the proper antiproliferative response in lesion-derived VSMCs, but by itself, the adequate level is not sufficient to create a significant antiproliferative response to TGF-β due to a possible sequestration of Smad3 in cytosol and an impaired shuttling of phosphorylated Smad3 into the nucleus. Most likely, the sequestration of Smad3 in cytoplasm is not the only, or main, reason for the lack of an antiproliferative response in resistant cells expressing Smad3.