The goal of this project is to characterize the mechanisms that regulate growth of vascular smooth muscle cells (VSMC) in vivo and in vitro. Because I wish to become an academic cardiologist, one of the major goals of my research training is to understand the cell biology of atherosclerosis and restenosis. I have chosen to study VSMC growth because I believe that this will provide me an important foundation for future work. Excessive growth of vascular smooth muscle cells (VSMC) in response to mitogens is important in disease processes such as restenosis, hypertension and atherosclerosis. Recent data indicate that a family of mitogen activated protein (MAP) kinases are stimulated in a sustained manner (>2 hr) by mitogens. In contrast we found that MAP kinase activation by the non-mitogenic peptide, angiotensin II, is transient (<30 min). This difference may be related to activity of an angiotensin II-stimulated, transcriptionally regulated, MAP kinase phosphatase (MKP-I) that inactivates MAP kinase. The major hypotheses of this proposal are that inhibiting expression of MKP-1 will """"""""convert"""""""" angiotensin II into a VSMC mitogen, and that overexpressing MKP-I will block mitogen-induced VSMC proliferation. To prove these hypotheses we will inhibit MKP-1 by """"""""knocking out"""""""" expression of MKP-1 in VSMC using antisense oligonucleotides, and examine the effect on in vitro and in vivo (after balloon injury) VSMC growth. In addition, we will determine the effect of overexpressing MKP-1 on angiotensin II-stimulated VSMC growth in vitro, and on the extent of neointimal proliferation after balloon injury of the rat carotid. The cellular and molecular approaches utilized in the proposed research will provide me with the tools I will need to pursue my goal of studying the molecular mechanisms that regulate growth in the cardiovascular system.
| Ishida, T; Ishida, M; Suero, J et al. (1999) Agonist-stimulated cytoskeletal reorganization and signal transduction at focal adhesions in vascular smooth muscle cells require c-Src. J Clin Invest 103:789-97 |
