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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.<\/jats:p>","DOI":"10.1530\/rep-20-0447","type":"journal-article","created":{"date-parts":[[2020,10,12]],"date-time":"2020-10-12T10:14:39Z","timestamp":1602497679000},"page":"31-41","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-11","source":"Crossref","is-referenced-by-count":8,"title":["Constitutive LH receptor activity impairs NO-mediated penile smooth muscle relaxation"],"prefix":"10.1093","volume":"161","author":[{"given":"Deepak S","family":"Hiremath","sequence":"first","affiliation":[{"name":"Department of Physiology , Southern Illinois School of Medicine, Carbondale, Illinois, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernanda B M","family":"Priviero","sequence":"additional","affiliation":[{"name":"Cardiovascular Translational Research 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