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Keywords:

  • RhoA/ROCK;
  • GPR30/GPER1;
  • Bladder Smooth Muscle Cells;
  • Estrogens

ABSTRACT

Introduction.  In male, lower urinary tract symptoms (LUTS) have been associated, beside benign prostatic hyperplasia, to some unexpected comorbidities (hypogonadism, obesity, metabolic syndrome), which are essentially characterized by an unbalance between circulating androgens/estrogens. Within the bladder, LUTS are linked to RhoA/Rho-kinase (ROCK) pathway overactivity.

Aim.  To investigate the effects of changing sex steroids on bladder smooth muscle.

Methods.  ERα, ERβ, GPR30/GPER1 and aromatase mRNA expression was analyzed in male genitourinary tract tissues, and cells isolated from bladder, prostate, and urethra. Estrogen and G1 effect on RhoA/ROCK signaling output like cell migration, gene expression, and cytoskeletal remodeling, and [Ca2+]i was also studied in hB cells. Contractile studies on bladder strips from castrated male rats supplemented with estradiol and testosterone was also performed.

Main Outcome Measures.  The effects of classical (ERα, ERβ) and nonclassical (GPR30/GPER1) estrogen receptor ligands (17β-estradiol and G1, respectively) and androgens on RhoA/ROCK-.mediated cell functions were studied in hB cells. Contractility studies were also performed in bladder strips from castrated male rats supplemented with testosterone or estradiol.

Results.  Aromatase and sex steroid receptors, including GPR30, were expressed in human bladder and mediates several biological functions. Both 17β-estradiol and G1 activated calcium transients and induced RhoA/ROCK signaling (cell migration, cytoskeleton remodeling and smooth muscle gene expression). RhoA/ROCK inhibitors blunted these effects. Estrogen-, but not androgen-supplementation to castrated rats increased sensitivity to the ROCK inhibitor, Y-27632 in isolated bladder strips. In hB cells, testosterone elicited effects similar to estrogen, which were abrogated by blocking its aromatization through letrozole.

Conclusion.  Our data indicate for the first time that estrogen-more than androgen-receptors up-regulate RhoA/ROCK signaling. Since an altered estrogen/androgen ratio characterizes conditions, such as aging, obesity and metabolic syndrome, often associated to LUTS, we speculate that a relative hyperestrogenism may induce bladder overactivity through the up-regulation of RhoA/ROCK pathway. Chavalmane AK, Comeglio P, Morelli A, Filippi S, Fibbi B, Vignozzi L, Sarchielli E, Marchetta M, Failli P, Sandner P, Saad F, Gacci M, Vannelli GB, and Maggi M. Sex steroid receptors in male human bladder: Expression and biological function. J Sex Medical 2010;7:2698–2713.