Circulation, Vol 87, 184-191, Copyright © 1993 by American Heart Association
KL March, BL Patton, RL Wilensky and DR Hathaway
BACKGROUND. Smooth muscle cell proliferation plays a major role in the
genesis of restenosis after angioplasty or vascular injury. Although the
effects of arterial exposure to high-energy radiation sources such as laser
have been investigated in detail, the effects on vascular cells of
low-intensity radiant energy in combination with photoactive agents have
not been extensively characterized. Psoralens are photoactive agents that
are known to be well tolerated when used in conjunction with local exposure
to ultraviolet light in the A band (UVA) for the treatment of various
dermatologic proliferative disorders. METHODS AND RESULTS. We have
investigated the effects of psoralen/UVA (PUVA) exposure on the
proliferation of bovine aortic smooth muscle cells. Proliferation and
viability were assessed over a 14-day period by trypan blue exclusion
counts. Cell cycle effects were evaluated by thymidine incorporation and
flow cytometry with DNA quantitation after addition of serum or
platelet-derived growth factor B-chain (PDGF-BB) to subconfluent cells
synchronized by serum withdrawal. No effect was observed after exposure to
8-methoxypsoralen (8-MOP) at concentrations up to 10 microM or UVA
irradiation at energies up to 2.5 J/cm2. Longwave ultraviolet light and
8-MOP were found to behave synergistically as potent inhibitors of DNA
synthesis in bovine aortic smooth muscle cells with the EC50 in combination
ranging from 7 microM at 0.35 J/cm2 to 0.2 microM at 2.1 J/cm2. Similar
antiproliferative effects were obtained by an inverse variation of dose and
energy delivered. After serum stimulation, inhibition of DNA synthesis was
found with either an immediate or delayed (16-hour) application of PUVA.
This effect was independent of subsequent 8-MOP washout. Flow cytometry of
cells treated with PUVA at several times after serum stimulation
demonstrated for each time point a block in further cell cycle progression
for cells in all phases of the cell cycle. Evaluation of [125I]-labeled
PDGF and epidermal growth factor (EGF) binding revealed no effect of PUVA
on the apparent number or affinity of PDGF binding sites present but did
reveal a dose-dependent inhibition by PUVA of EGF binding. This inhibition
of EGF binding occurred increasingly at higher PUVA doses than the cell
cycle inhibition and accordingly did not appear to represent a critical
mechanism for the antiproliferative effect. Cell counting after a single
exposure to PUVA (1 microM, 1.5 J/cm2) revealed complete stasis of cell
proliferation over a 28-day period without recurrent exposure. No increase
in trypan-positive cells was noted over this period. CONCLUSIONS. PUVA
treatment represents a novel method for locally inhibiting proliferation of
vascular smooth muscle cells without producing cytolysis.
ARTICLES
8-Methoxypsoralen and longwave ultraviolet irradiation are a novel antiproliferative combination for vascular smooth muscle
Krannert Institute of Cardiology, Indianapolis, Ind. 46202-4800.
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