Effects of hypercholesterolemia on monokine-induced smooth muscle cell proliferation

Macrophage/smooth muscle cell interactions play a role in atherogenesis and foreign body reactions to biomaterials. This study investigates the effect of a hypercholesterolemic diet on the ability of smooth muscle cells (SMCs) to respond to monokines which are produced in response to hypercholesterolemia, biomaterials or both. Peritoneal macrophages were harvested from rabbits fed either a normal (M phi NL) or a 2% cholesterol/6% peanut oil diet (M phi ATH) (plasma cholesterol 2840 vs 42.3 [p less than 0.005]). The macrophages were then cultured in the presence of either 1) polyglactin 910 (PG910), 2) Dacron, or 3) no biomaterial (control), and the media collected and pooled by week for the smooth muscle cell mitogenesis assays. Rabbit aortic smooth muscle cells were harvested and cultured from the same two groups of rabbits (SMCNL or SMCATH), quiesced in serum free media (48 h) followed by addition of the test media and 3H-TdR. The addition of either biomaterial to M phi NL-conditioned media increased 3H-TdR incorporation in both smooth muscle lines as compared to controls. PG910 resulted in significantly higher 3H-TdR incorporation than Dacron (weeks 3-5, p less than 0.005). The addition of either biomaterial to M phi ATH also increased 3H-TdR incorporation in both smooth muscle cell lines, however, the magnitude of the response was decreased as compared to the M phi NL-conditioned media in both cell lines (p less than 0.001 for either SMC line). In contrast to the M phi NL-conditioned media, the addition of Dacron to M phi ATH resulted in the highest level of 3H-TdR incorporation in both cell lines as compared to the media without biomaterial. The SMCNL had a higher response to both the monokines in conditioned media (2-fold) and to fetal bovine serum (3-fold) than the SMCATH (p less than 0.001). Although there is a generalized decrease in release of mitogens active on SMCs from M phi ATH, the M phi ATH exposed to Dacron release increased amounts of mitogenic factors, most active on the SMCATH cell line. A common mode of failure of small diameter Dacron grafts in man is pseudointimal hyperplasia, and it is inviting to postulate that the Dacron/macrophage/smooth muscle cell interactions in this atherosclerotic group of patients plays a role in the pathogenesis of this lesion.