Phytoestrogen derivatives differentially inhibit arterial neointimal proliferation in a mouse model.
Neointimal proliferation is a key element in atherosclerotic plaque formation and in arterial restenosis following angioplasty. Estrogen-like compounds, including naturally occurring plant phytoestrogens, are known to alter the extent of neointimal proliferation. This study investigates the anti-atherogenic/restenotic effect of several synthetic metabolites of isoflavone phytoestrogens (dihydrodaidzein, tetrahydrodaidzein and dehydroequol) (Novogen, Sydney, Australia). Acute neointimal proliferation was induced in the iliac artery of cholesterol-fed mice, by mechanically damaging the endothelium. Phytoestrogens were administered orally for 4 weeks and the damaged arteries harvested. Intimal area, as a percentage of the iliac artery wall area, was measured. Dihydrodaidzein significantly halved the intimal response (intima approximately 25% of wall area; p < 0.01) compared with placebo diet-fed mice (intima approximately 50% of wall area), while tetrahydrodaidzein and dehydroequol showed no inhibitory effects. Immunohistochemistry demonstrated that alpha-actin-positive vascular smooth muscle cells were the major cell type in the proliferating neointima. A single layer of endothelium covered the thickened intima by 4 weeks. Thus, a specific phytoestrogen isoflavone compound (dihydrodaidzein) can selectively inhibit neointimal proliferation, either by inhibition of vascular smooth muscle cell migration and proliferation, and/or by enhancing endothelial proliferation and function, and inhibition of endothelial apoptosis.
Shen
Jie
J
Discipline of Pathology, School of Medical Sciences, Faculty of Medicine, University of Sydney 2006, Australia.
White
Melanie
M
Husband
Alan J
AJ
Hambly
Brett D
BD
Bao
Shisan
S
D017130:Angioplasty / Q000009:adverse effects; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D023903:Coronary Restenosis / Q000517:prevention & control; D007083:Iliac Artery / Q000187:drug effects / Q000473:pathology; D007529:Isoflavones / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology; D048789:Phytoestrogens / Q000494:pharmacology; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D007529:Isoflavones; D048789:Phytoestrogens; C433165:dehydroequol; C433163:dihydrodaidzein; C433164:tetrahydrodaidzein