Constitutive LH receptor activity impairs NO-mediated penile smooth muscle
Authors Hiremath DS, Priviero FBM, Webb RC, Ko C, Narayan P
Submitted By Submitted Externally on 1/5/2021
Status Published
Journal Reproduction (Cambridge, England)
Year 2021
Date Published 1/1/2021
Volume : Pages 161 : 31 - 41
PubMed Reference 33112284
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 GMP (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.