Integrin Adhesion Complex Organization in Sheep Myometrium Reflects Changing Mechanical Forces during Pregnancy and Postpartum

SIMPLE SUMMARY: IACs assemble within the sheep myometrium during early-to-mid gestation in response to increased stretch of the uterine wall and continue to increase as pregnancy progresses. Fibronectin (FN1) is important in its ability to attach to IACs in myometrial cells to generate force to sustain powerful contractions during labor. After parturition, IACs are disassembled but the integrin subunits ITGA5 and ITGB1 remain expressed at the protein level at least two weeks postpartum. ABSTRACT: Cells respond to extracellular mechanical forces through the assembly of integrin adhesion complexes (IACs) that provide a scaffold through which cells sense and transduce responses to those forces. IACs are composed of transmembrane integrin receptors that bind to extracellular matrix (ECM) proteins externally and connect with the actomyosin cytoskeleton internally. Myometrial smooth muscle cells respond to forces that arise due to increases in fetal growth/weight, placental fluid volumes, and blood flow. As a result, the uterus transforms into an organ that can forcefully expel the fetus and placental membranes during parturition. While earlier studies focused on IAC expression in the myometrial compartment of rodents and humans to explore pregnancy-associated responses, the present study examines IAC assembly in ovine myometrium where mechanical forces are expected to be amplified in a manner similar to humans. Results indicate that the ITGA5 and ITGB1 heterodimers associate with the ECM protein FN1 externally, and with VCL and TLN1 internally, to form IACs in myometrial cells during the first trimester of pregnancy. These IACs become increasingly ordered until parturition. This ordered structure is lost by one day postpartum; however, the abundance of the integrin proteins remains elevated for at least two weeks postpartum. Implications of the present study are that sheep are similar to humans regarding the assembly of IACs in the pregnant myometrium and suggest that IACs may form much earlier in human gestation than was previously implied by the rat model. Results highlight the continued value of the sheep model as a flagship gynecological model for understanding parturition in humans.