Figure 5. Uterine HIF2α places the implanting embryo in the bottom of the endometrial crypt through induction of LIF.

(A) The positioning of embryo attachment at the bottom of the endometrial crypt was impaired in Hif2a-uKO mice at 1000 hours on day 5. Scale bar, 100 μm; arrowhead, an embryo; s, stroma; le, luminal epithelium. (B and C) COX2, a marker of embryo attachment reaction, was similarly expressed in the implantation sites of both Hif2a-uKO and control mice. P > 0.05, n ≥ 5, mean ± SEM, Student’s t test. (D) The expression of LIF, a key regulator of embryo attachment, was decreased at the implantation site of Hif2a-uKO mice on day 5 morning. *P < 0.05, n ≥ 5, mean ± SEM, Student’s t test. (E) Activation of STAT3, a downstream signaling of LIF, was eliminated in the implantation site of Hif2a-uKO mice, as demonstrated by phosphorylated STAT3 immunostaining. (F) Intraperitoneal injection of recombinant LIF (20 μg/mouse on day 4) into Hif2a-uKO mice in addition to P₄ injection normalized the position of embryo attachment to the bottom of the endometrial crypt on day 5 morning. (G) LIF administration could not rescue implantation failure in Hif2a-uKO mice on day 6 morning (arrow, a destroyed embryo with blood cell infiltration).