Pregnancy success in mice requires appropriate cannabinoid receptor signaling for primary decidua formation

An early event after implantation is stromal cell transformation to decidual cells (decidualization) that support embryo development. In mice, this process begins at the antimesometrial (AM) pole with differentiation of stromal cells into epithelial-like cells (epithelioid cells) surrounding the implantation chamber. This is an avascular zone called the primary decidual zone (PDZ), and considered to function as a transient, size-dependent permeable barrier to protect the embryo from maternal circulating harmful agents, including immunoglobulins, immune cells, microorganisms and other noxious agents. This zone forms on day 5 afternoon and becomes fully established on day 6 with the loss of the crypt epithelium. The PDZ gradually degenerates with the appearance of the secondary decidual zone (SDZ) around the PDZ that peaks on day 8 in mice. Decidualization is critical for early pregnancy in mice and humans. We show that cannabinoid/endocannabinoid signaling influences decidualization in early pregnancy. Mice deficient in two major cannabinoid receptors, CB1 and CB2, show compromised PDZ. We found that angiogenic factors are dysregulated in Cnr1-/-Cnr2-/- mice with defective PDZs, resulting in the abnormal presence of blood vessels and macrophages in this zone; disruption of the PDZ compromises pregnancy outcomes. Using an in vitro decidualization model, we found that Cnr1 levels increase in mouse stromal cells and human uterine fibroblast (Huf) cells undergoing decidualization and that limiting CB1 signaling in these cell types suppresses decidualization in vitro. Since endothelial cells express Cnr2 and decidual cells express Cnr1, we hypothesize that angiogenic events driven by CB2 are integrated with CB1 in decidual cells, leading to proper PDZ formation, a critical step for pregnancy success.