|Authors||Chambliss KL, Wu Q, Oltmann S, Konaniah ES, Umetani M, Korach KS, Thomas GD, Mineo C, Yuhanna IS, Kim SH, Madak-Erdogan Z, Maggi A, Dineen SP, Roland CL, Hui DY, Brekken RA, Katzenellenbogen JA, Katzenellenbogen BS, Shaul PW|
|Journal||J. Clin. Invest. Volume: 120 Issue: 7 Pages: 2319-30|
|Publish Date||2010 Jul|
Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ERalpha, direct ERalpha-Galphai interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ERalpha- and G protein-dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer.
|Full Text||Full text available on PubMed Central|