Department of Physiology, Southern Illinois School of Medicine, Carbondale, Illinois, USA.
Cardiovascular Translational Research Center and Department of Cell Biology and Anatomy University of South Carolina, Columbia, South Carolina, USA.
Reproduction. 2021 Jan;161(1):31-41. doi: 10.1530/REP-20-0447.
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.
黄体生成素受体（LHCGR）的及时激活对于生育能力至关重要。LHCGR 的激活突变导致家族性男性局限性早熟（FMPP），因为睾酮的过早合成。我们实验室之前开发了一种 FMPP 的小鼠模型（KiLHRD582G），该模型表达 LHCGR 的组成性激活突变。由于性功能障碍，KiLHRD582G 小鼠逐渐不育，并表现出阴茎平滑肌丧失和软骨细胞积累。在这项研究中，我们测试了 KiLHRD582G 小鼠由于平滑肌功能障碍而患有勃起功能障碍的假设。阿扑吗啡诱导的勃起研究确定 KiLHRD582G 小鼠患有勃起功能障碍。使用阴茎海绵体条评估阴茎平滑肌和内皮功能。KiLHRD582G 小鼠的阴茎内皮细胞含量没有变化。乙酰胆碱和一氧化氮供体硝普钠的最大松弛反应在 KiLHRD582G 小鼠中显着降低，表明一氧化氮（NO）介导的信号转导受损。KiLHRD582G 小鼠对乙酰胆碱、硝普钠和可溶性鸟苷酸环化酶刺激剂 BAY 41-2272 的反应中，环鸟苷酸（cGMP）水平显着降低。NOS1、NOS3 和 PKRG1 的表达没有变化。平滑肌收缩的 Rho-激酶信号通路没有改变。总之，这些数据表明，由于 NO 介导的可溶性鸟苷酸环化酶激活受损导致 cGMP 水平降低和阴茎平滑肌松弛，KiLHRD582G 小鼠发生勃起功能障碍。这些在 KiLHRD582G 小鼠中的研究表明，LHCGR 中的激活突变导致小鼠勃起功能障碍，原因是阴茎平滑肌中的 NO 介导的信号通路受损。
