Phytoestrogens inhibit growth and MAP kinase activity in human aortic smooth muscle cells

Estrogens are known to induce cardioprotective effects by inhibiting smooth muscle cell (SMC) growth and neointima formation, However, the use of estr ogens as cardioprotective agents is limited by carcinogenic effects in wome n and feminizing effects in men. If noncarcinogenic and nonfeminizing estro genlike compounds, such as natural phytoestrogens, afford cardioprotection, this would provide a safe method for prevention of cardiovascular disease in both men and women. Therefore, we evaluated and compared in human aortic SMCs the effects of phytoestrogens (formononetin, genistein, biochanin A, daidzein, and equol) on 2.5% fetal calf serum-induced proliferation (H-3-th ymidine incorporation and cell number), collagen synthesis (H-3-proline inc orporation), and total protein synthesis (H-3-leucine incorporation) and on PDGF-BB (25 ng/mL)-induced migration (modified Boydens chambers). Moreover , the effects of phytoestrogens on PDGF-BB (25 ng/ml)-induced mitogen-activ ated protein kinase (MAP kinase) activity in SMCs was also studied. Phytoes trogens inhibited proliferation, collagen and total protein synthesis, migr ation, and MAP kinase activity in a concentration-dependent manner and in t he following order of potency: biochanin a>genistein>equol>daidzein>formono netin. In conclusion, our studies provide the first evidence that in human aortic SMCs phytoestrogens inhibit mitogen-induced proliferation, migration and extracellular matrix synthesis and inhibit/ downregulate MAP kinase ac tivity. Thus, phytoestrogens may confer protective effects on the cardiovas cular system by inhibiting vascular remodeling and neointima formation and way be clinically useful as a safer substitute for feminizing estrogens in preventing cardiovascular disease in both women and men.