In 2002, arterial occlusion accounted for 30% of U.S. deaths and $200 billion in cost. The major therapy for the disease, angioplasty, is used only in advanced cases and has a failure rate of 30-50%. Recent research has shown that this failure is due to remodeling, a process involving all layers of the arterial wall at the geometric and the cellular level. Its complexity implies a coordination among the layers of the vessel wall and their cell types. The precise mechanism of this communication is essentially unexplored. The applicant seeks to test the hypothesis that transforming growth factor-beta (TGF-b) acts on the smooth muscle cells of the medial layer through SmadS, an intracellular protein, to secrete connective tissue growth factor (CTGF), that then induces changes in the fibroblasts of the adventitial layer. SmadS-overexpressing smooth muscle cells will be stimulated with TGF-b; fibroblasts will be exposed to the conditioned media with or without a specific CTGF inhibitor, and will then be assessed for changes typical of remodeling. Fibroblasts will then be stimulated with pure CTGF for comparison. CTGF production in an animal angioplasty model, and the affect of smadS overexpression and exogenous CTGF on remodeling, will be examined. ? ? ?
| Tsai, Shirling; Hollenbeck, Scott T; Ryer, Evan J et al. (2009) TGF-beta through Smad3 signaling stimulates vascular smooth muscle cell proliferation and neointimal formation. Am J Physiol Heart Circ Physiol 297:H540-9 |
| Kundi, Rishi; Hollenbeck, Scott T; Yamanouchi, Dai et al. (2009) Arterial gene transfer of the TGF-beta signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF. Cardiovasc Res 84:326-35 |
