A murine model of
vascular injury-induced neointimal
hyperplasia was developed by using a photoactive
dye,
rose bengal. Photoactivation of
rose bengal induced
vascular injury to the femoral arteries of C57B1/6 mice and resulted in an occlusive neointimal
hyperplasia after 4 weeks. The cellular elements of the hyperplastic
neointima were found to be
alpha-actin-positive vascular smooth muscle cells expressing
epidermal growth factor (
EGF) receptor at high levels.
EGF-Gen, an
EGF-R-specific inhibitor with potent anticancer activity, suppressed the formation of hyperplastic
neointima. Morphometric analysis of serial tissue sections at 4 weeks after
vascular injury showed that in 75% of the
EGF-Gen-treated mice, the maximal
stenosis index was only 0.44 +/- 0.13, whereas in 75% of
phosphate-buffered saline (PBS)-treated mice, the maximal
stenosis index was 1.20 +/- 0.25. The mean
neointima/media 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 group (
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 treatment of mice with
vascular injury to the left femoral artery was not associated with any clinical signs of toxicity or histopathologic lesions in any of the organs, including the uninjured right femoral artery.
EGF-Gen also inhibited VSMC migration in vitro, without affecting VSMC proliferation and viability, suggesting that
EGF-Gen is blocking
neointima formation by inhibiting 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.