Constitutive LH receptor activity impairs NO-mediated penile smooth muscle relaxation

Abstract

Timely activation of the luteinizing hormone receptor (LHCGR) is critical for fertility. Activating mutations in LHCGR cause familial male-limited precocious puberty (FMPP) due to premature synthesis of testosterone. A mouse model of FMPP (KiLHRD582G), expressing a constitutively activating mutation in LHCGR, was previously developed in our laboratory. KiLHRD582G mice became progressively infertile due to sexual dysfunction and exhibited smooth muscle loss and chondrocyte accumulation in the penis. In this study we tested the hypothesis that KiLHRD582G mice had erectile dysfunction due to impaired smooth muscle function. Apomorphine-induced erection studies determined that KiLHRD582G mice had erectile dysfunction. Penile smooth muscle and endothelial function were assessed using penile cavernosal strips. Penile endothelial cell content was not changed in KiLHRD582G mice. The maximal relaxation response to acetylcholine and the nitric oxide donor, sodium nitroprusside, was significantly reduced in KiLHRD582G mice indicating an impairment in the nitric oxide (NO)- mediated signaling. Cyclic guanosine monophosphate (cGMP) levels were significantly reduced in KiLHRD582G mice in response to acetylcholine, sodium nitroprusside and the soluble guanylate cyclase stimulator, BAY 41-2272. Expression of NOS1, NOS3 and PKRG1 were unchanged. The Rho-kinase signaling pathway for smooth muscle contraction was not altered. Together, these data indicate that KiLHRD582G mice have erectile dysfunction due to impaired NO-mediated activation of soluble guanylate cyclase resulting in decreased levels of cGMP and penile smooth muscle relaxation. These studies in the KiLHRD582G mice demonstrate that activating mutations in the mouse LHCGR cause erectile dysfunction due to impairment of the NO-mediated signaling pathway in the penile smooth muscle.

The role of red ginseng in men’s reproductive health: a literature review

“…Nitric oxide synthase (NOS), which includes neuronal NOS and endothelial NOS, uses L-arginine as a substrate to generate NO from oxygen; acetylcholine may also facilitate NO production and release. The released NO activates guanylate cyclase in the smooth muscle cytoplasm to produce cyclic guanosine monophosphate (cGMP) [ 85 ]. RG may act by releasing or enhancing the endothelial cell relaxing factor and increasing acetylcholine-induced rabbit cavernous muscle relaxation, which may be mediated by NO and/or cGMP [ 49 ] (Fig.…”

Infiltration of inflammatory factors induced penile damage in chronic prostatitis

“…We further analysed the expression of vasodilation related proteins, consisting of iNOS, eNOS and nNOS. Nitric Oxide (NO), as an inorganic substance, plays an important role in erectile function through cyclic GMP (cGMP) level changes (Deepak et al, 2021). It was reported that the down-regulation of eNOS…”