Aviv Hassid, Ph.D., Bronstein Professor of Cardiovascular Physiology
Associate Director, Vascular Biology Center of Excellence

Migration of smooth muscle cells is of critical importance to vascular development, angiogenesis, neointima formation and the tissue remodeling that occurs after vascular injury. Preliminary observations indicate that NO elicits reorganization of the actin cytoskeleton and that it increases the motility of rat aortic smooth muscle cells in primary culture, but not subculture. These effects are associated with increased levels of protein tyrosine phosphatase 1D (SHP2) in primary culture but not subculture. We have found that a reduction of SHP2 protein levels with antisense oligodeoxynucleotide (ODN) attenuates NO- induced motility in primary cultures. Our goal is to investigate the role of SHP2 in NO-induced cell motility in culture and in vivo. My research can be divided into three interrelated parts which are described in detail.

A. Mechanisms of NO-stimulated SHP2 expression: A1) Determine whether NO increases SHP2 enzyme activity, concomitantly with increased protein levels. A2) Determine whether NO increases SHP2 mRNA levels and if so, whether this effect requires cGMP-dependent protein kinase (PKG) activity. If mRNA levels are increased, determine whether increased mRNA synthesis can explain this effect or whether increased mRNA stability may be involved. A3) Determine whether NO increases the rate of SHP2 synthesis and/or decreases the rate of SHP2 metabolism.

B. Consequences of gain-of-function or loss-of-function of PKG or SHP2 in cultured cells: B1) Determine whether enforced expression of PKG in subcultured cells deficient in PKG restores the capacity of NO to increase SHP2 protein levels and stimulate cell motility. B2) Determine whether enforced expression of wild-type SHP2, but not catalytically inactive mutant SHP2, in subcultured cells deficient in SHP2 enhances cell motility. B3) Determine whether NO-elicited actin cytoskeletal reorganization and increased cell motility in primary culture are blocked by agents that interfere with SHP2 function and whether over-expression of SHP2 mimics the effects of NO.

C. Expression of SHP2 and modulation of cell motility by SHP2 in vivo: Determine whether vascular injury increases SHP2 protein levels and whether expression of dominant-interfering mutant of SHP2 attenuates vascular injury- induced cell motility and neointima formation. We anticipate that this project will provide new information on mechanisms that are likely to explain the motogenic capacity of NO in aortic smooth muscle cells and in vivo: Determine whether vascular injury increases SHP2 protein levels and whether expression of dominant-interfering mutant of PTP1D attenuates vascular injury-induced cell motility and neointima formation. We anticipate that this project will provide new information on mechanisms that are likely to explain the motogenic capacity of NO in aortic smooth muscle cells and in vivo.

Recent Publications

Yellaturu CR, Ghosh SK, Rao RK, Jennings LK, Hassid A and Rao GN. A potential role for nuclear factor of activated T cells in receptor tyrosine kinase and G protein-coupled receptor agonist-induced cell proliferation. Biochem J 368:183-190, 2002.

Bhanoori M, Yellaturu CR, Ghosh SK, Hassid A, Jennings LK and Rao GN. Thiol alkylation inhibits the mitogenic effects of platelet-derived growth factor and renders it proapoptotic via activation of STATs and p53 and induction of expression of caspase1 and p21waf1/cip1. Oncogene 22(1):117-30, 2003.

Chang Y, Ceacareanu B, Dixit M, Sreejayan N and Hassid A. Nitric oxide-induced motility in aortic smooth muscle cells: role of protein tyrosine phosphatase SHP-2 and GTP-binding protein Rho. Circ Res 91:390-397, 2002.

Protein-tyrosine phosphatase-1B (PTP1B) mediates the anti-migratory actions of Sprouty. Yigzaw Y, Poppleton HM, Sreejayan N, Hassid A and Patel TB. J Biol Chem 278(1):284-288, 2003.

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