Uterine scarring leads to adverse pregnant consequence through impairing the response of endometrium to steroids

Uterine surgical scarring is an increasing risk factor for adverse
pregnant consequences that threaten fetal-maternal health. The detailed
molecular features of scar implantation remain largely unknown. We aim to
study the pathologic features of uterine surgical scarring and the
mechanisms of compromised pregnancy outcomes of scar implantation. We
generated a mouse model of uterine surgical scarring with a uterine
incision penetrating the myometrium to endometrium to examine the
pathologic changes and transcriptome profiles of uterine scarring at
various post-surgery (PS) time points, as well as features of the
feto-maternal interface during scar implantation. We found that uterine
surgical scar recovery was consistently poor at PS3 until PS90, as shown
by a reduced number of endometrial glands, inhibition of myometrial smooth
muscle cell growth but excessive collagen fiber deposition, and massive
leukocyte infiltration. Transcriptome annotation indicated significant
chronic inflammation at the scarring site. At the peri-implantation and
postimplantation stages, abnormal expression of various steroid-responsive
genes at the scarring site was in parallel with lumen epithelial cell
hyperplasia, inappropriate luminal closure, and disorientation of the
implanted embryo, restricted stromal cell proliferation, and defective
decidualization. High embryonic lethality (around 70%) before E10.5 was
observed, and the small amount of survival embryos at E10.5
exhibited restricted growth and aberrant placenta defects
including overinvasion of trophoblast cells into the decidua and
insufficient fetal blood vessel branching in the labyrinth. The findings
indicate that chronic inflammation and compromised responses to steroids
in uterine scar tissues are the pivotal molecular basis for adverse
pregnancy consequences of scar implantation.