Differential Expression of Fibulin Family Proteins in Mechanically Strong vs. Weak Fetal Membrane Fragments

Abstract

Untimely rupture of the fetal membranes (FM), the amnion and choriodecidua, which normally surround and protect the fetus prior to delivery, is a major cause of preterm birth and results in significant infant mortality and morbidity. The physiological mechanism which normally leads the FM to weaken and fail prior to birth is not known. Conventional thinking that FM rupture is precipitated by the stress of uterine contractions during labor fails to explain the 10% of term deliveries and 40% of preterm deliveries in which FM rupture is the sentinel event, preceding any uterine contractions. Recent studies from several laboratories indicate that the FM undergo a genetically-programmed, biochemically-mediated, maturation process, near term, which is characterized by collagen remodeling and apoptosis. In human FM, in contrast to rat membranes, these changes are limited to the region of the FM overlying the cervix [1]. In a series of publications, our group has demonstrated that human FM have a zone of physical weakness (decreased force to rupture and work to rupture relative to the other areas of the same FM) overlying the cervical opening of the uterus. We further demonstrate that this same zone is characterized by specific markers of increased collagen remodeling and apoptosis [1–3]. These regional characteristics develop prior to the onset of contractions of labor and persist until delivery. Furthermore, the rupture tear line of the FM intersects this weak zone and thus the rupture process is hypothesized to initiate in this weak zone [3]. In order to investigate how differences in the biochemical composition of the extra-cellular matrix of the weak and the strong zones of FM reflect their different biomechanical properties, we utilized a proteomics approach to identify differences in the abundance of specific proteins in weak and strong FM fragments. Initial 2-DIGE screening resolved differences in Fibulin 5 protein expression. This prompted further analysis of additional members of the Fibulin protein family.