Role of fibulin-5 insufficiency and prolapse progression on murine vaginal biomechanical function

Abstract

The vagina plays a critical role in supporting the pelvic organs and loss of support leads to pelvic organ prolapse. It is unknown what microstructural changes influence prolapse progression nor how decreased elastic fibers contributes to vaginal remodeling and smooth muscle contractility. The objective for this study was to evaluate the effect of fibulin-5 haploinsufficiency, and deficiency with progressive prolapse on the biaxial contractile and biomechanical function of the murine vagina. Vaginas from wildtype (n = 13), haploinsufficient (n = 13), and deficient mice with grade 1 (n = 9) and grade 2 or 3 (n = 9) prolapse were explanted for biaxial contractile and biomechanical testing. Multiaxial histology (n = 3/group) evaluated elastic and collagen fiber microstructure. Western blotting quantified protein expression (n = 6/group). A one-way ANOVA or Kruskal–Wallis test evaluated statistical significance. Pearson’s or Spearman’s test determined correlations with prolapse grade. Axial contractility decreased with fibulin-5 deficiency and POP (p < 0.001), negatively correlated with prolapse grade (ρ = − 0.80; p < 0.001), and positively correlated with muscularis elastin area fraction (ρ = − 0.78; p = 0.004). Circumferential (ρ = 0.71; p < 0.001) and axial (ρ = 0.69; p < 0.001) vaginal wall stresses positively correlated with prolapse grade. These findings demonstrated that fibulin-5 deficiency and prolapse progression decreased vaginal contractility and increased vaginal wall stress. Future work is needed to better understand the processes that contribute to prolapse progression in order to guide diagnostic, preventative, and treatment strategies.

Collagen organization and structure inFLBN5-/-, mice using label-free microscopy: implications for pelvic organ prolapse

“…KO mice functionally lack elastic fibers that provide mechanical support to soft tissues, limiting the ability of the ECM to recover from deformation in response to applied forces. Without functional and fully assembled elastic fibers, fibrillar collagen, which largely provides the ECM tensile strength, is left to bear increased loading distinct in KO compared to HET soft tissue [9]. Indeed, in vivo and in vitro fibulin-5 HET mouse cervices display significantly greater circumferential contractility than fibulin-5 KO mouse cervices [40].…”

“…Clark-Patterson et al . demonstrated significantly reduced collagen alignment ratio with respect to the circumferential and axial axes in KO murine vaginas compared to FBLN5 +/- (HET) murine vaginas [9]. Furthermore, Budatha et al .…”

The mechanism of adipose mesenchymal stem cells to stabilize the immune microenvironment of pelvic floor injury by regulating pyroptosis and promoting tissue repair

“…Strong mechanical force may cause acute dilation, overstretch, or even fracture of the pelvic floor tissue during the second stage of labor, resulting in damage to pelvic floor tissue. The role of mechanical force injury in the pathogenesis of POP has been gradually uncovered in recent years [ 5 , [42] , [43] , [44] ]. Mechanical injury leads to oxidative stress in the pelvic floor support structure, causing ROS accumulation and ECM metabolic disorder.…”

Collagen organization and structure in FBLN5-/- mice using label-free microscopy: implications for pelvic organ prolapse

“…Fibulin-5 is a glycoprotein produced in smooth muscle cells, fibroblasts, or vascular endothelial cells [ 7 ] that is responsible for proper elastic fiber formation [ 8 ]. Elastic fiber components such as elastin, fibulins, and fibrillins are critical to proper extracellular matrix (ECM) construction, contributing mechanical compliance and elasticity to the reproductive tract [ 9 ]. For example, loss of elastic fibers in arterial walls decreases collagen fiber undulation that affects the collagen fiber’s stiffening characteristics [ 10 ].…”

“…Consequently, collagen can be remodeled in the KO reproductive tract. Clark-Patterson et al demonstrated significantly reduced collagen alignment ratio with respect to the circumferential and axial axes in KO murine vaginas compared to FBLN5 +/- (HET) murine vaginas [ 9 ]. Furthermore, Budatha et al reported thin and contorted collagen fibers in murine KO vaginas [ 11 ].…”