Atherosclerosis, a major disease of the elderly, involves both proliferative, as well as degenerative changes in arteries. We originally hypothesized that the control of proliferation of vascular SMCs (SMC) is distrubed with aging, resulting in excessive proliferative responses. The evidence to date indicates that the proliferation of vascular SMCs is significantly increased for old animals in three experimental paradigms: following 1) arterial injury, 2) aortic transplantation of old to young, 3) serum- free culture of SMC in vitro. This data strongly suggests an autocrine basis for the old/young disparity. SMC from old animals show enhanced proliferation compared to young SMC, probably due to production by old SMC of a PDGF-like growth factor. In addition, old SMC produce less growth inhibitory substances that young SMC. Exogenous heparin corrects the imbalance, suggesting that normal mitogenic signals are 'disinhibited' with aging. We propose to examine systemically the effects of purified mitogens and inhibitors or the growth of old and young SMC in vitro. Age-related proliferative changes will be examined at the biochemical and molecular level, with special attention directed at the abnormal expression of autrocrine growth factor genes (c- sis and PDGF A-chain). We will also extend our animal model to include studies of in vivo arterial injury; comparing in young and old animals the rates of reendothelialization, extracellular matrix composition, inhibitory effect of non-anticoagulant heparins, as well as the proliferative properties of EC and SMC in vitro. Both normolipemic and hypercholesterolmic subjects will be examined, thereby expanding our understanding of the interaction of other atherogenic risk factors in this model. The proposed studies are directed toward elucidation of the molecular control of SMC proliferation during the aging process.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL035724-05
Application #
3349920
Study Section
Pathology A Study Section (PTHA)
Project Start
1985-09-30
Project End
1993-09-29
Budget Start
1989-09-30
Budget End
1990-09-29
Support Year
5
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Rimarachin, J A; Jacobson, J A; Szabo, P et al. (1994) Regulation of cyclooxygenase-2 expression in aortic smooth muscle cells. Arterioscler Thromb 14:1021-31
McCaffrey, T A; Falcone, D J; Borth, W et al. (1994) Alpha 2-macroglobulin/transforming growth factor-beta 1 interactions. Modulation by heparin-like molecules and effects on vascular smooth muscle cells. Ann N Y Acad Sci 737:368-82
Falcone, D J; McCaffrey, T A; Haimovitz-Friedman, A et al. (1993) Macrophage and foam cell release of matrix-bound growth factors. Role of plasminogen activation. J Biol Chem 268:11951-8
Szabo, P; Weksler, D; Whittington, E et al. (1993) The age-dependent proliferation of rat aortic smooth muscle cells is independent of differential splicing of PDGF A-chain mRNA. Mech Ageing Dev 67:79-89
Rimarachin, J A; Norcross, J; Szabo, P et al. (1992) GAPDH acts as an inducible not constitutive gene in cultured endothelial cells. In Vitro Cell Dev Biol 28A:705-7
McCaffrey, T A; Falcone, D J; Borth, W et al. (1992) Fucoidan is a non-anticoagulant inhibitor of intimal hyperplasia. Biochem Biophys Res Commun 184:773-81
Falcone, D J; McCaffrey, T A; Vergilio, J A (1991) Stimulation of macrophage urokinase expression by polyanions is protein kinase C-dependent and requires protein and RNA synthesis. J Biol Chem 266:22726-32
McCaffrey, T A; Falcone, D J; Brayton, C F et al. (1989) Transforming growth factor-beta activity is potentiated by heparin via dissociation of the transforming growth factor-beta/alpha 2-macroglobulin inactive complex. J Cell Biol 109:441-8
McCaffrey, T A; Agarwal, L A; Weksler, B B (1988) A rapid fluorometric DNA assay for the measurement of cell density and proliferation in vitro. In Vitro Cell Dev Biol 24:247-52
McCaffrey, T A; Nicholson, A C; Szabo, P E et al. (1988) Aging and arteriosclerosis. The increased proliferation of arterial smooth muscle cells isolated from old rats is associated with increased platelet-derived growth factor-like activity. J Exp Med 167:163-74

Showing the most recent 10 out of 11 publications