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(American Journal of Pathology. 2007;170:578-589.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060662

Pelvic Organ Prolapse in Fibulin-5 Knockout Mice

Pregnancy-Induced Changes in Elastic Fiber Homeostasis in Mouse Vagina

Peter G. Drewes*, Hiromi Yanagisawa{dagger}, Barry Starcher{ddagger}, Ian Hornstra§, Katalin Csiszar, Spyridon I. Marinis*, Patrick Keller* and R. Ann Word*

From the Departments of Obstetrics and Gynecology* and Molecular Biology,{dagger} University of Texas Southwestern Medical Center, Dallas, Texas; the Department of Biochemistry,{ddagger} University of Texas Health Science Center, Tyler, Texas; the Department of Medicine/Dermatology,§ Washington University School of Medicine, St. Louis, Missouri; and the Cardiovascular Research Center, John A. Burns School of Medicine, University of Hawaii, Manoa, Honolulu, Hawaii

Pelvic organ prolapse is strongly associated with a history of vaginal delivery. The mechanisms by which pregnancy and parturition lead to failure of pelvic organ support, however, are not known. Recently, it was reported that mice with null mutations in lysyl oxidase-like 1 (LOXL1) develop pelvic organ prolapse. Elastin is a substrate for lysyl oxidase (LOX) and LOXL1, and LOXL1 interacts with fibulin-5 (FBLN5). Therefore, to clarify the potential role of elastic fiber assembly in the pathogenesis of pelvic organ prolapse, pelvic organ support was characterized in Fbln5–/– mice, and changes in elastic fiber homeostasis in the mouse vagina during pregnancy and parturition were determined. Pelvic organ prolapse in Fbln5–/– mice was remarkably similar to that in primates. The temporal relationship between LOX mRNA and protein, processing of LOXL1 protein, FBLN5 and tropoelastin protein, and desmosine content in the vagina suggest that a burst of elastic fiber assembly and cross linking occurs in the vaginal wall postpartum. Together with the phenotype of Fbln5–/– mice, the results suggest that synthesis and assembly of elastic fibers are crucial for recovery of pelvic organ support after vaginal delivery and that disordered elastic fiber homeostasis is a primary event in the pathogenesis of pelvic organ prolapse in mice.




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