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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:2323-2329.)
© 1999 American Heart Association, Inc.

Vascular Biology

Autocrine FGF-2 Is Responsible for the Cell Density–Dependent Susceptibility to Apoptosis of HUVEC

A Role of a Calpain Inhibitor–Sensitive Mechanism

Mikio Kinoshita; Kentaro Shimokado

From the National Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan.

Correspondence to Kentaro Shimokado, MD, National Cardiovascular Center Research Institute, Fujishirodai 5-7-1, Suita, Osaka 565-8565, Japan. E-mail kshimoka{at}res.ncvc.go.jp

Abstract—To elucidate the factors affecting endothelial susceptibility to apoptosis, we studied the effects of cell density on endothelial cell apoptosis induced by deprivation of serum and fibroblast growth factor-2 (FGF-2/basic FGF). On deprivation, more cells became apoptotic in a dense culture (5x10² cells/mm²) than in a sparse culture (1x10² cells/mm²) of human umbilical vein endothelial cells. FGF-2, hepatocyte growth factor, and vascular endothelial cell growth factor, but not insulin-like growth factor-I, decreased apoptosis in the dense culture to a level similar in the sparse culture. An anti–FGF-2 antibody significantly increased the apoptosis in the sparse culture, suggesting that the sparse culture was resistant to apoptosis because of the greater autocrine production of FGF-2. Western blot analysis and metabolic labeling revealed that the sparse culture has, in fact, more FGF-2 than the dense culture. The steady state level of mRNA for FGF-2 was not significantly different between the dense and sparse cultures. Among a panel of inhibitors for 2 major cytoplasmic proteolytic enzymes, calpain inhibitors increased FGF-2 in the dense culture, but proteasome inhibitors did not. Our findings demonstrate that cell density affects endothelial survival by regulating autocrine FGF-2 production through a calpain inhibitor–sensitive mechanism.

Key Words: apoptosis • growth factors • cytoplasmic neutral protease • endothelial integrity • endothelial cells

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