Dr. Ronald Jenkins' long-term goals center on furthering the understanding of the arterial responses to injury as they relate to the development of atherosclerosis. The hyperproliferative response to balloon injury responsible for reclosure of coronary arteries following angioplasty (restenosis) provides an opportunity to study the effectors of accelerated cell and matrix accumulation which appear to be basic mechanisms of atherosclerosis. Recent information suggests that the regulatory protein transforming growth factor-beta (TGF-beta) plays a central role in this process. Blocking antibody to TGF-beta has in turn been shown in-vitro to inhibit pathologic matrix accumulation in certain tissues. TGF-beta is produced by smooth muscle cells which are known to produce similar matrix components. The proposed research will define the relationship of TGF-beta to the synthesis of matrix proteoglycans and proteins in excised rings from normal and balloon-injured rabbit aorta physiologically maintained in-vitro. At intervals following injury, metabolic labeling, SDS-PAGE, fluorography and immunohistochemistry will be used to identify, and quantitate newly synthesized matrix products and cell proliferation. The stimulation of matrix production will be correlated with neointimal thickening in-vivo assessed by intravascular ultrasound, a novel technique for real-time in-vivo morphometric analysis. Agents known to antagonize TGF-beta expression, such as anti- TGF-beta antibodies, and decorin, a small matrix proteoglycan, will be tested both in vitro and in-vivo for effectiveness in decreasing matrix production and neointimal proliferation in balloon injured rabbit aorta. Fortuitously, the refinement of an atherosclerotic rabbit aorta experimental model in Dr. Jenkins' laboratory coincides with the demonstration of the role of TGF-beta in glomerular mesangial cells by Dr. Wayne Border's laboratory. While the ultimate focus of this collaboration will be to develop pharmacologic means to arrest neointimal thickening following balloon injury, these studies will have applicability to atherosclerosis, if not all processes of wound healing.
