The Role of Estrogen Receptor alpha and beta in Regulating Vascular Smooth Muscle Cell Proliferation is Based on Sex

Background. We previously demonstrated that vascular smooth muscle cells (VSMC) proliferation and development of neointimal hyperplasia as well as the ability of nitric oxide (NO) to inhibit these processes is dependent on sex and hormone status. The aim of this study was to evaluate the role of estrogen receptor (ER) in mediating proliferation in male and female VSMC. Materials and Methods. Proliferation was assessed in primary rat aortic male and female VSMC using 3 H-thymidine incorporation in the presence or absence of ER alpha (alpha) inhibitor methyl-piperidinopyrazole, the ER beta (beta) inhibitor (R, R)-5,11-Diethyl-5,6,11,12- tetrahydro-2,8-chrysenediol, the combined ER alpha beta inhibitor ICI 182,780, and/or the NO donor DETA/NO. Proliferation was also assessed in primary aortic mouse VSMC harvested from wildtype (WT), ER alpha knockout (ER alpha KO), and ER beta knockout (ER beta KO) mice in the presence or absence of DETA/NO and the ER alpha, ER beta, and ER alpha beta inhibitors. Protein levels were assessed using Western blot analysis. Results. Protein expression of ER alpha and ER beta was present and equal in male and female VSMC, and did not change after exposure to NO. Inhibition of either ER alpha or ER beta had no effect on VSMC proliferation in the presence or absence of NO in either sex. However, inhibition of ER alpha beta in rat VSMC mitigated NO-mediated inhibition in female but not male VSMC (P<0.05). Evaluation of proliferation in the knockout mice revealed distinct patterns. Male ER alpha KO and ER beta KO VSMC proliferated faster than male WT VSMC (P < 0.05). Female ER beta KO proliferated faster than female WT VSMC (P < 0.05), but female ER alpha KO VSMC proliferated slower than female WT VSMC (P<0.05). Last, we evaluated the effect of combined inhibition of ER alpha and ER beta in these knockout strains. Combined ER alpha beta inhibition abrogated NO-mediated inhibition of VSMC proliferation in female WT and knockout VSMC (P<0.05), but not in male VSMC. Conclusions. These data clearly demonstrate a role for the ER in mediating VSMC proliferation in both sexes. However, these data suggest that the antiproliferative effects of NO may be regulated by the ER in females but not males. Published by Elsevier Inc.

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