Lower urogenital tract anatomical and functional phenotype in lysyl oxidase like-1 knockout mice resembles female pelvic floor dysfunction in humans

Abstract

Female pelvic floor dysfunction (FPFD) is a complex group of conditions that include urinary incontinence and pelvic organ prolapse (POP). In humans, elastin homeostasis has been implicated in the pathophysiology of FPFD. Lysyl oxidase-like 1 knockout (LOXL1-KO) mice demonstrate abnormal elastic fiber homeostasis and develop FPFD after parturition. We compared the lower urogenital tract (LUT) anatomy and function in LOXL1-KO mice with and without POP. LUT anatomy was assessed in LOXL1-KO mice over 28 wk. Pelvic visceral anatomy in LOXL1-KO was evaluated with a 7-Tesla magnetic resonance imaging (MRI) scanner. LUT function was assessed using conscious cystometry and leak point pressure (LPP) testing. Quantitative histological analysis of elastic fibers was performed on external urethral sphincter (EUS) cross sections. By 25 wk of age, 50% of parous LOXL1-KO mice developed POP. LOXL1-KO mice with POP had greater variability in the size and location of the bladder on MRI compared with mice without POP. Parity and POP were associated with lower LPP. Elastin clusters were significantly increased in the EUS of LOXL1-KO mice with POP. Because parity triggers POP in LOXL1-KO mice, LOXL1-KO mice with POP have variable internal pelvic anatomy, and both parity and POP are associated with a decrease in LPP, we conclude that LOXL1 LUT anatomical and functional phenotype resembles FPFD in humans. The increase in elastin clusters in the urethra of LOXL1-KO mice with POP suggests that elastin disorganization may lead to functional abnormalities. We conclude that LOXL1 warrants further investigation in the pathphysiology of FPFD.

Vaginal wall weakness in parous ewes: a potential preclinical model of pelvic organ prolapse

“…NHP are often considered ideal; however, they are not strictly bipedal, they are small, and their Post hoc Jonkheere-Terpstra: *P < 0.05; **P, 0.01, ***P < 0.0001 compared with nulliparous cost is extremely limiting [23]. The pelvic floor anatomy of rodents is more horizontal than that in humans, and offspring have a much smaller fetal head-to-birth-canal ratio [24]. Their small size makes it almost impossible for clinical examination or surgery to compare with humans.…”

Effect of Pregnancy and Delivery on Cytokine Expression in a Mouse Model of Pelvic Organ Prolapse

“…22,25 Additionally, this data helps further explain our previous study of lower urinary tract function in Loxl1 KO mice in which we showed that parity significantly contributed to lower leak point pressures. 12 Overall, our data suggest that Loxl1 deficiency results in aberrant antepartum and postpartum gene expression responses to pregnancy and parturition that may be exacerbated by vaginal delivery.…”

“…14,28 In addition, POP in Loxl1 KO mice simulates the phenotype of POP in women, with vaginal delivery as a major risk factor, often affecting voiding function, and progressing with age. 1,11,12 …”

“…15 Similar to women, parity is the leading risk factor for POP in Loxl1 KO mice and POP is delayed, but not prevented, by cesarean delivery. 11,12 In addition, the prolapse rate in Loxl1 KO mice increases with age, and presents with variable prolapse grades and incidences (50–80%). 16,17 …”

Levormeloxifene inhibits vaginal tropoelastin and transforming growth factor beta 1 production

“…Ewies et al (2003) and Karam et al (2007) demonstrated ) knockout mice with evidence of disrupted elastin fibers (Drewes et al, 2007). Lysyl oxidase-like1 (LOXL1) is a protein involved in the elastin fiber synthesis and assembly and LOXL1 knockout mice exhibit significant elastin fiber defects and POP in the postpartum period (Lee et al, 2008). POP has also been associated with cutis laxa, a genetic disorder with unclear etiology but associated with markedly decreased elastin (Paladini et al, 2007).…”