Elastin homeostasis is altered with pelvic organ prolapse in cultures of vaginal cells from a lysyl oxidase‐like 1 knockout mouse model. Issue 11 (12th June 2020) - Jameson, Slater A.
Abstract: Pelvic organ prolapse (POP) decreases quality of life for many women, but its pathophysiology is poorly understood. We have previously shown that Lysyl oxidase‐like 1 knockout ( Loxl1 KO) mice reliably prolapse with age and increased parity, similar to women. Both this model and clinical studies also indicate that altered elastin metabolism in pelvic floor tissues plays a role in POP manifestation, although it is unknown if this is a cause or effect. Using Loxl1 KO mice, we investigated the effects of genetic absence of Loxl1, vaginal parity, and presence of POP on the expression of genes and proteins key to the production and regulation of elastic matrix. Cultured cells isolated from vaginal explants of mice were assayed with Fastin for elastic matrix, as well as RT‐PCR and Western blot for expression of genes and proteins important for elastin homeostasis. Elastin synthesis significantly decreased with absence of LOXL1 and increased with parity ( p < .001), but not with POP. Cells from prolapsed mice expressed significantly decreased MMP‐2 ( p < .05) and increased TIMP‐4 ( p < .05). The results suggest changes to elastin structure rather than amounts in prolapsed mice as well as poor postpartum elastin turnover, resulting in accumulation of damaged elastic fibers leading to abnormal tropoelastin deposition. POP may thus, be the result of an inability to initiate the molecular mechanisms necessary to clear and replace damaged elastic matrix in pelvic floor tissues after vaginal birth. Abstract : The disruption of normal elastic fiber homeostasis has been implicated in clinical manifestation of pelvic organ prolapse (POP). In this controlled study, we sought to ascertain the individual contributions of vaginal birth (parity), prolapse, and LOXL1 absence on maintenance of elastic fiber homeostasis, in a LOXL1 KO mouse model. Group‐wise comparisons relevant to each of these three effects are indicated by the respective colored arrows. We investigated changes in elastic matrix synthesis, cell proliferation, gene (RT‐PCR) and protein (western blots) expression for key elastic fiber assembly proteins, enzymes regulating matrix proteolysis and key signaling proteins (TGF‐B1 and BMP‐1) known to be implicated in elastin homeostasis. Primary outcomes pertinent to the three effects are indicated in the callouts. Our results suggest that the combination of inhibited elastin precursor synthesis, impaired cross‐linking, and poor elastin clearing creates an environment in which the vaginal ECM cannot properly repair itself after each delivery. Successive trauma sustained to the pelvic floor without proper repair could lead to POP.