Blockade of growth factor synthesis and growth factor action: two possible sites of interference in allograft vessel disease and coronary bypass or balloon injury.
When injured, vascular endothelial cells produce growth factors that cause smooth muscle cells (SMC) to migrate from the media to the intima of the vessel wall, replicate in the intima, and stimulate arteriosclerotic changes. Interference with the actions of growth factors in allograft arteriosclerosis was explored. The somatostatin analog angiopeptin was administered to allograft-recipient rats after transplantation of aortic allografts between major and minor histoincompatible rat strains. Levels of epidermal growth factor (EGF), insulin-like growth factor-1 (IGF-1), and platelet-derived growth factor (PDGF) in grafts from 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 response was also investigated. SMC cultures were serum-deprived of growth 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 substrate 1 (IRS-1) and IGF-1R phosphorylation in vitro. Infusion of JB3 into rats undergoing balloon dilatation injury inhibited SMC replication in the injured vascular area by nearly 70%, but inhibited intimal thickening by only 30%. In conclusion, interference in the growth factor response may be one way of reducing/preventing vascular injury. However, blockade of more than one growth factor may be needed to achieve an optimal effect.
Häyry
P
P
Transplantation Laboratory, University of Helsinki, Finland.
Aavik
E
E
Myllärniemi
M
M
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000637:transplantation*; D001161:Arteriosclerosis / Q000473:pathology*; D001808:Blood Vessels / Q000293:injuries*; D002404:Catheterization; D002455:Cell Division / Q000187:drug effects; D001026:Coronary Artery Bypass; D004815:Epidermal Growth Factor / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology*; D006133:Growth Substances / Q000096:biosynthesis / Q000502:physiology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D051381:Rats; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors; D013002:Somatomedins / Q000494:pharmacology; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014184:Transplantation, Homologous
D006131:Growth Inhibitors; D006133:Growth Substances; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010982:Platelet-Derived Growth Factor; D017451:Receptors, Somatomedin; D013002:Somatomedins; C060347:lanreotide; D013004:Somatostatin; D004815:Epidermal Growth Factor; D007334:Insulin-Like Growth Factor I