Androgen Effects on the Adrenergic System of the Vascular, Airway, and Cardiac Myocytes and Their Relevance in Pathological Processes

Figure 2

Androgen effects on the adrenergic system in the vascular smooth muscle (VSM). (a) Stimulation of the β-adrenergic receptor (β-AR) leads to an increase in the activity of the K⁺ channels and to plasma membrane hyperpolarization. β-AR receptor is coupled to a Gs protein (Gs) that activates adenylyl cyclase (AC), which enhances the synthesis of 3′,5′-cyclic adenosine monophosphate (cAMP) and consequently promotes the protein kinase A- (PKA-) induced phosphorylation of the K⁺ channels. K⁺ channel phosphorylation increases their open probability and evokes membrane hyperpolarization that closes Ca²⁺ channels, leading to vasorelaxation. Testosterone, via a rapid response (nongenomic), activates ATP-sensitive K⁺ channels (K_ATP), Ca²⁺-activated K⁺ channels of high conductance (BK_Ca), and voltage-dependent delayed rectifier K⁺ channels (K_V). Dihydrotestosterone (DHT, a reduced metabolite of T) enhances the activity of the K_V channel. T also blocks VDCCs. Androgen-induced vasorelaxation mediated by the activation of K⁺ channels and the blockade of VDCCs might improve the response of β-AR signaling. (b) The genomic androgen receptor (AR) signaling involves androgen crossing the plasma membrane, entering the cytoplasm, dissociation of chaperone proteins, and binding to its cytosolic receptor. AR stimulation by T  results in a decrement of AC expression and a reduction of cAMP synthesis. Moreover, T increases the α₁-adrenergic receptor (α₁-AR) expression. This receptor is coupled to a Gq protein (Gq), which, through phospholipase C_β (PLC_β), catalyzes the formation of inositol-1, 4, 5-triphosphate (IP₃) and triggers intracellular calcium release from the sarcoplasmic reticulum (SR). The genomic effects of T favor vasoconstriction in the VSM and might lead to hypertension development.