Failure of heparin to inhibit intimal hyperplasia in injured baboon arteries. The role of heparin-sensitive and -insensitive pathways in the stimulation of smooth muscle cell migration and proliferation.

Abstract

Heparin is a potent inhibitor of smooth muscle cell (SMC) growth and intimal hyperplasia in animal models but has been ineffective in inhibiting restenosis in humans. This difference may relate to flaws in clinical study design or, alternatively, to interspecies differences in SMC response to heparin. To determine whether heparin could inhibit intimal hyperplasia in a species more closely related to humans, we studied the effect of a low-molecular-weight heparin (LMWH) on baboon SMC proliferation and migration in culture and in arteries subjected to experimental angioplasty. LMWH or saline was infused continuously after experimental angioplasty of baboon peripheral arteries (six animals per group). After 28 days, bromodeoxyuridine (BrdU) was given to label proliferating cells, and balloon-injured arteries were perfusion-fixed in situ and removed for analysis. All arteries had reendothelialized (Evans blue dye exclusion). LMWH increased partial thromboplastin time (LMWH, 81.7 +/- 8.4 seconds versus saline, 34.7 +/- 0.8 seconds [mean +/- SEM]; P = .004) but failed to inhibit intimal thickening or SMC proliferation (intimal area: LMWH, 0.19 +/- 0.03 mm2 versus saline, 0.21 +/- 0.03 mm2; BrdU labeling: LMWH, 2.9 +/- 0.6% versus saline, 2.4 +/- 0.4%; P = NS). In culture, LMWH and standard heparin (100 micrograms/mL) significantly inhibited serum-induced but not platelet-derived growth factor (PDGF-BB)-induced SMC proliferation (% control, serum: LMWH, 60.5 +/- 4.0%, P = .0002; standard heparin, 29.4 +/- 8.2%, P = .0001; % control, PDGF-BB: LMWH, 117.7 +/- 11.3%, P = NS; standard heparin, 90.9 +/- 14.4%, P = NS) and SMC migration (% control, serum: LMWH, 15.3 +/- 1.9%, P = .0198; standard heparin, 26.4 +/- 13.8%, P = .0032; % control, PDGF-BB: LMWH, 98.5 +/- 14.3%, P = NS; standard heparin, 100.0 +/- 13.5%, P = NS). LMWH failed to inhibit intimal hyperplasia in a baboon angioplasty model. Furthermore, LMWH blocked serum-induced but not PDGF-BB-induced SMC proliferation and migration in culture. Thus, heparin-sensitive and -insensitive pathways exist for SMC activation. The relative importance of each pathway induced by injury may vary between species and thus account for different responses to heparin.