AMINO-ACID DEPLETION MODULATES VASCULAR ENDOTHELIAL GROWTH-FACTOR PRODUCTION DURING THE LIFE-SPAN OF HUMAN VASCULAR SMOOTH-MUSCLE CELLS

The role of nutrient supply in the replicative capacity and secretory phenotype of cultured human diploid cells is unclear. We examined the relationship between amino acid privation, the secretion of vascular e ndothelial growth factor (VEGF) and growth phenotype of vascular smoot h muscle cells (VSMC), and endothelial cells. Cultures of VSMCs, but n ot endothelial cells, were growth inhibited by exposure to medium that was 75% deficient in leucine, methionine, arginine, and cysteine over two passages. Exposed VSMC cultures exhibited an increased vulnerabil ity to apoptosis. The maximal cumulative population doubling of the ex posed cells was reduced significantly compared with the control cells (25.7 +/- 2.0 doublings vs. 27.9 +/- 2.1 doublings; P<0.03). Constitut ive VEGF production first became evident in the later passages of the exposed and nonexposed cell cultures. However, production of VEGF was 17-fold greater in the exposed cultures at the tenth passage (P < 0.00 1). The replicative capacity and constitutive production of VEGF in VS MCs in culture may be programmed by transient privation of amino acids . These observations are relevant to new concepts concerning the patho genesis of Vascular disease. (C) 1998 Wiley-Liss, Inc.