BLOCKADE OF GROWTH-FACTOR SYNTHESIS AND GROWTH-FACTOR ACTION - 2 POSSIBLE SITES OF INTERFERENCE IN ALLOGRAFT VESSEL DISEASE AND CORONARY-BYPASS OR BALLOON INJURY

When injured, vascular endothelial cells produce growth factors that c ause smooth muscle cells (SMC) to migrate from the media to the intima of the vessel wall, replicate in the intima, and stimulate arterioscl erotic changes. Interference with the actions of growth factors in all ograft arteriosclerosis was explored. The somatostatin analog angiopep tin was administered to allograft-recipient rats after transplantation of aortic allografts between major and minor histoincompatible rat st rains. Levels of epidermal growth factor (EGF), insulin-like growth fa ctor-1 (IGF-1), and platelet-derived growth factor (PDGF) in grafts fr om angiopeptin-treated recipients were 35% to 75% of levels in grafts from nontreated recipients. Replication of SMC in the media and intima was reduced by 30% to 90% and intimal thickening by approximately 50% , The effect of blockade of IGF-1 receptors (IGF-1R) on the intimal re sponse was also investigated. SMC cultures were serum-deprived of grow th factors, then stimulated to replicate by addition of PDGF-B and EGF . Anti-IGF-1 and anti-IGF-1R antibodies reduced SMC replication by 50% and 90%, respectively. A D-amino acid analog of IGF-1, JB3, inhibited SMC replication and dose-dependently inhibited insulin receptor subst rate 1 (IRS-1) and IGF-1R phosphorylation in vitro. Infusion of JB3 in to rats undergoing balloon dilatation injury inhibited SMC replication in the injured vascular area by nearly 70%, but inhibited intimal thi ckening by only 30%. In conclusion, interference in the growth factor response may be one way of reducing/preventing vascular injury, Howeve r, blockade of more than one growth factor may be needed to achieve an optimal effect. Copyright (C) 1996 by W.B. Saunders Company