Crucial role of androgen receptor in vascular H 2 S biosynthesis induced by testosterone

Background and Purpose Hydrogen sulphide ( H 2 S ) is a gaseous mediator strongly involved in cardiovascular homeostasis, where it provokes vasodilatation. Having previously shown that H 2 S contributes to testosterone‐induced vasorelaxation, here we aim to uncover the mechanisms underlying this effect. Experimental Approach H 2 S biosynthesis was evaluated in rat isolated aortic rings following androgen receptor ( NR3C4 ) stimulation. Co‐immunoprecipitation and surface plasmon resonance analysis were performed to investigate mechanisms involved in NR3C4 activation. Key Results Pretreatment with NR3C4 antagonist nilutamide prevented testosterone‐induced increase in H 2 S and reduced its vasodilator effect. Androgen agonist mesterolone also increased H 2 S and induced vasodilatation; effects attenuated by the selective cystathionine‐γ lyase ( CSE ) inhibitor propargylglycine. The NR3C4 ‐multicomplex‐derived heat shock protein 90 (hsp90) was also involved in this effect; its specific inhibitor geldanamycin strongly reduced testosterone‐induced H 2 S production. Neither progesterone nor 17‐β‐oestradiol induced H 2 S release. Furthermore, we demonstrated that CSE , the main vascular H 2 S ‐synthesizing enzyme, is physically associated with the NR3C4 /hsp90 complex and the generation of such a ternary system represents a key event leading to CSE activation. Finally, H 2 S levels in human blood collected from male healthy volunteers were higher than those in female samples. Conclusions and Implications We demonstrated that selective activation of the NR3C4 is essential for H 2 S biosynthesis within vascular tissue, and this event is based on the formation of a ternary complex between cystathionine‐γ lyase, NR3C4 and hsp90. This novel molecular mechanism operating in the vasculature, corroborated by higher H 2 S levels in males, suggests that the L ‐cysteine/ CSE / H 2 S pathway may be preferentially activated in males leading to gender‐specific H 2 S biosynthesis. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6