SERUM AND PLATELET-DERIVED GROWTH FACTOR-INDUCED EXPRESSION OF VASCULAR-PERMEABILITY FACTOR MESSENGER-RNA BY HUMAN VASCULAR SMOOTH-MUSCLE CELLS IN-VITRO

1. Endothelial dysfunction and vascular smooth muscle cell (VSMC) prol iferation are key events in the pathogenesis of atherosclerosis, Vascu lar permeability factor (VPF), an endothelial-cell-specific multifunct ional cytokine, was recently described, and has the potential to contr ibute to the development of endothelial dysfunction, The present study determines whether cultured human VSMCs express mRNA for VPF and whet her VPF mRNA expression is influenced by human VSMC proliferation. 2. A 204 bp cDNA fragment, specific for all known variants of VPF mRNA, w as cloned and used to demonstrate that human VSMCs express abundant qu antities of VPF mRNA, whereas human endothelial cells do not, VPF mRNA levels were markedly diminished in non-proliferating human VSMCs, In contrast, when human VSMCs were stimulated to proliferate by exposure to serum, there was a rapid 6.6-fold increase (P<0.01 versus time O h) in VPF mRNA expression, which was maximal at 3 h and persisted beyond 24 h. The magnitude of the VPF mRNA response in human VSMCs was depen dent on the serum concentration. 3. Platelet-derived growth factor als o increased VPF mRNA expression by human VSMCs, thus confirming that r ecognized growth factors for VSMCs also potently influence the VPF gen e. 4. In conclusion, VPF mRNA is expressed by human VSMCs, the magnitu de of VPF expression being temporally related to the proliferation of human VSMCs and the potency of the growth-promoting stimulus, We propo se that VPF produced by proliferating human VSMCs could act as a parac rine hormone to powerfully influence the permeability and growth of th e overlying vascular endothelium. We thus report a novel mechanism whe reby the stimulation of VSMC proliferation could potently and directly contribute to the development of endothelial dysfunction and the path ogenesis of vascular disease.