Uterine injury during diestrus leads to embryo spacing defects and perturbations in the Cox-2 pathway in subsequent pregnancies

Uterine injury from procedures such as Cesarean sections (C-sections) often have severe consequences on subsequent pregnancy outcomes, leading to disorders such as placenta previa, placenta accreta, and infertility. With rates of C-section at approximately 30% of deliveries in the US that are projected to continue to climb, an understanding of the mechanisms by which these pregnancy disorders arise and opportunities for intervention are sorely needed. However, there are currently no animal models to date that comprehensively assess the consequences of uterine injury. Here we describe the first rodent model of uterine injury on subsequent in utero outcomes. We observed four distinct phenotypes: reduced implantation events, increased rates of resorption, embryo misspacing, and placenta accreta-like features of reduced decidua and expansion of invasive trophoblasts. We also show that the appearance of embryo misspacing depends entirely on the phase of estrous cycle at the time of injury, leading us to identify differences in uterine wound healing as a function of estrous. Using RNA-seq, we identified perturbations in the expression of components of the COX-2 pathway after recovery from injury, a pathway that has previously been demonstrated to play an important role in embryo spacing. Therefore, we demonstrate that uterine damage in our novel mouse model engenders many uterine changes, most notably perturbed expression of COX-2 pathway-related genes, that ultimately lead to numerous placental and embryonic developmental defects with parallels to human pregnancy disorders. mRNA profiles of mouse uterine mRNA collected from untreated animals or after >1 mo. of recovery post-diestrus or estrus injury