Differential effect of Photofrin II on growth of human smooth muscle cells from nonatherosclerotic arteries and atheromatous plaques in vitro.

Abstract

The effect of dihematoporphyrin-ester or -ether (DHE), a photosensitizing porphyrin with different amounts of aggregates, on the growth of cultured smooth muscle cells obtained from nonatherosclerotic arteries and from atheromatous plaques (primary stenosing and restenosing lesions) was examined without photoactivation of the drug. Clinically relevant DHE concentrations ranging from 0.1 to 25 micrograms/ml were used. In all proliferation studies with cells of second and third passage (approximately 10 cumulative population doublings in vitro), the growth rates decreased in a dose-dependent manner. Smooth muscle cells from atherosclerotic lesions were significantly more sensitive than smooth muscle cells from normal arteries. Cells derived from restenosing lesions retained their increased sensitivity even after eight passages in culture (approximately 20 cumulative population doublings). Cell size measurements showed that the decreased proliferative activity mainly occurred in smooth muscle cell subpopulations consisting of small cells. A cytotoxic effect of DHE was observed at concentrations above 5 micrograms/ml, causing cytoplasmic protrusions, vacuoles, and even complete cell lysis. At a DHE concentration of 5 micrograms/ml, the number of viable cells was 73% +/- 14% (means +/- SD) for smooth muscle cells from nonatherosclerotic arterial media and only 38% +/- 11% (means +/- SD) for smooth muscle cells from atherosclerotic plaques. In all experiments, no significant difference in response to DHE treatment was observed between cells from primary stenosing and restenosing lesions, suggesting a specific mechanism for plaque-derived cells causing an increased sensitivity in comparison to smooth muscle cells from nonatherosclerotic arteries. The pronounced sensitivity of plaque cells against DHE treatment suggests that this drug--even without photoactivation--is potentially valuable in vivo as a therapeutic approach to vascular stenoses.