EGF-Genistein inhibits neointimal hyperplasia after vascular injury in an experimental restenosis model

A murine model of vascular injury-induced neointimal hyperplasia was develo ped by using a photoactive dye, rose bengal. Photoactivation of rose bengal induced vascular injury to the femoral arteries of C57B1/6 mice and result ed in an occlusive neointimal hyperplasia after 4 weeks. The cellular eleme nts of the hyperplastic neointima were found to be alpha-actin-positive vas cular smooth muscle cells expressing epidermal growth factor (EGF) receptor at high levels. EGF-Gen, an EGF-R-specific inhibitor with potent anticance r activity, suppressed the formation of hyperplastic neointima. Morphometri c analysis of serial tissue sections at 4 weeks after vascular injury showe d that in 75% of the EGF-Gen-treated mice, the maximal stenosis index was o nly 0.44 +/- 0.13, whereas in 75% of phosphate-buffered saline (PBS)-treate d mice, the maximal stenosis index was 1.20 +/- 0.25. The mean neointima/me dia ratios for areas of maximum neointimal hyperplasia were 0.59 +/- 0.16 ( n = 24) for the EGF-Gen-treated group, 0.99 +/- 16 (n = 45) for the PBS gro up (EGF-Gen vs. PBS, p = 0.0017), and 1.03 +/- 18 (n = 8) for group treated with unconjugated genistein (EGF-Gen vs. Gen, p = 0.0088). EGF-Gen treatme nt of mice with vascular injury to the left femoral artery was not associat ed with any clinical signs of toxicity or histopathologic lesions in any of the organs, including the uninjured right femoral artery. EGF-Gen also inh ibited VSMC migration in vitro, without affecting VSMC proliferation and vi ability, suggesting that EGF Gen is blocking neointima formation by inhibit ing cellular migration to vascular injury sites. In conclusion, EGF-Gen may be useful as a nontoxic prophylactic agent for prevention of restenosis in clinical settings.