Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival

Abstract

In the uterus, the formation of new maternal blood vessels in the stromal compartment at the time of embryonic implantation is critical for the establishment and maintenance of pregnancy. Although uterine angiogenesis is known to be influenced by the steroid hormones estrogen (E) and progesterone (P), the underlying molecular pathways remain poorly understood. Here, we report that the expression of connexin 43 (Cx43), a major gap junction protein, is markedly enhanced in response to E in uterine stromal cells surrounding the implanted embryo during the early phases of pregnancy. Conditional deletion of the Cx43 gene in these stromal cells and the consequent disruption of their gap junctions led to a striking impairment in the development of new blood vessels within the stromal compartment, resulting in the arrest of embryo growth and early pregnancy loss. Further analysis of this phenotypical defect revealed that loss of Cx43 expression resulted in aberrant differentiation of uterine stromal cells and impaired production of several key angiogenic factors, including the vascular endothelial growth factor (Vegf). Ablation of CX43 expression in human endometrial stromal cells in vitro led to similar findings. Collectively, these results uncovered a unique link between steroid hormone-regulated cell-cell communication within the pregnant uterus and the development of an elaborate vascular network that supports embryonic growth. Our study presents the first evidence that Cx43-type gap junctions play a critical and conserved role in modulating stromal differentiation, and regulate the consequent production of crucial paracrine signals that control uterine neovascularization during implantation.

The endometrium responds differently to cloned versus fertilized embryos

“…Similar to the present study, a striking increase of stromal GJA1 was observed in the intercaruncular and caruncular endometrial stroma at the onset of implantation between days 18 and 21 of pregnancy in sheep (34), suggesting that reduced GJA1 mRNA expression in bovine clone pregnancies may affect placentation negatively. Indeed, conditional deletion of the Gja1 gene in the stromal cells of the mouse uterus led to impaired production of key angiogenic factors and a striking impairment in the development of new blood vessels within the stromal compartment, resulting in the arrest of embryo growth and early pregnancy loss (35).…”

Estrogen-induced Expression of Fos-related Antigen 1 (FRA-1) Regulates Uterine Stromal Differentiation and Remodeling

“…The decidual tissue also undergoes extensive remodeling to control embryo invasion and accommodate the growing embryo. As the decidua forms around the implanted embryo, the uterine endothelial cells proliferate to create an extensive vascular network, which is embedded in the decidua and critical for embryo development (5,6). These morphological and functional changes in the pregnant uterus are regulated by the actions of the steroid hormones 17␤-estradiol (E) 2 and progesterone (P), which act via their cognate nuclear receptors to control the expression of critical gene networks (7).…”

Estradiol Reduces Connexin43 Gap Junctions in the Uterus during Adenomyosis in Cows

“…So far, Cx43 function have been described in connection with pregnancy and labor in human (Laws et al 2008), porcine (Romek and Karasiński 2011) and mouse (Doring et al 2006) uteri. All these studies reported an increase in Cx43 in the myometrium during term and preterm delivery as essential for the development of uterine contractions.…”