Vascular smooth muscle cell (VSMC) proliferation and migration has been proven to be a critical event in the development of varicosity. Variations in estrogen levels, a pathological event related to age and pregnancy, play a role in the pathogenesis of varicosity. Previous studies have reported a different response of VSMCs following estrogen stimulation. However, the exact mechanisms involved have not yet been elucidated. In the present study, we examined the responses of lesion and normal VSMCs treated with 10(-8) M 17β-estradiol (E2) for 24 h. A differential effect of exposure to E2 was observed in these cells. IQ-domain GTPase-activating protein 1 (IQGAP1), a scaffold protein, was overexpressed in the lesion VSMCs and was shown to modulate VSMC proliferation and migration in response to E2. Furthermore, the increased expression of IQGAP1 was found to be intimately associated with a high activity of estrogen receptor α (ERα), which has been implicated in the regulation of VSMC physiological function. Additionally, we found that two critical kinases, Akt and extracellular signal-regulated kinase (ERK), mediated the activation of ERα and VSMC proliferation. According to our results, we thus concluded that high levels of IQGAP1 in VSMCs regulate the physiological reaction of the cells in response to estrogen exposure, and that kinases are involved in the process by mediating ERα activation. In view of the essential role of IQGAP1 in the physiological function of VSMCs, targeting this molecule may prove to be a promising strategy for the treatment of varicosity.