Receptivity And Implantation Adhesion Cascade

Initial conceptus attachment requires loss of antiadhesive components, mainly mucins, contained in the glycocalyx of LE that sterically inhibit attachment.[1] The mucin, MUC1, exists as both an intrinsic transmembrane mucin and an alternatively spliced, secreted variant. Both forms are localized to the apical uterine LE to provide a barrier to attachment, but are generally reduced during the receptive phase (mice, pig, sheep) or locally at the site of blastocyst attachment (human, rabbit) due to activation of cell-surface proteases.

Unmasking adhesion molecules on the LE surface permits initial low-affinity contacts with Tr that are subsequently combined with or replaced by more stable adhesive interactions. In invasive implantation, these initial interactions precede a repertoire of trophoblast interactions with maternal extracellular matrix (ECM) and stromal cell populations encountered following intrusion beyond the LE.[6,7] Initial adhesion is mediated by molecules that contribute low affinity but specific carbohydrate ligand-binding, including selectins and galectins. Other molecules that have been implicated in implantation adhesion events include heparan sulfate proteoglycan, heparin-binding EGF-like growth factors, cadherins, and CD44. Low-affinity interactions are followed by stable adhesion.[6,7] In all mammals investigated, integrins expressed on blastocysts and uterine LE and their ECM ligands appear to be the dominant contributors to stable implantation adhesion systems by virtue of their roles in adhesion, migration, invasion, cytoskeletal organization, and bidirectional signaling.[8] In humans, expression of avp3 and a4p1 integrins increases in LE during the window of implantation.[7] These and other integrins identified at both maternal and conceptus interfaces along with integrin-binding matrix proteins such as fibronectin, oncofetal fibronectin, vitronectin, osteopontin (OPN), laminin, and the latency-associated peptide linked to transforming growth factor-(TGF-)beta are critical in both noninvasive and invasive implanting species.[8,9] These and other ECM constituents may function as bridging ligands for stable adhesion between apically expressed maternal and fetal integrins.

Global gene profiling using high-density microarray technology has identified genes that either increase or decrease during the window of implantation. Comparison of endometrial tissue between late proliferative phase and secretory phase human endometria identified 323 genes that increase and over 370 genes that decrease by at least twofold.[10] Modulated genes include cell-surface proteins/receptors, ECM molecules, secretory proteins, immune modulators/cytokines, cytoskeletal proteins, transporters, and transcription factors, as well as proteins involved in cholesterol trafficking, prostaglandin biosynthesis, detoxification, cell-cycle regulation, signal trans-duction, and other cellular functions. About 20% of the changes were attributed to genes encoding cell-surface receptors, adhesion and ECM proteins, and growth factors,[10] including markers of uterine receptivity in humans such as glycodelin and OPN, stromal cell-specific insulin growth factor-binding proteins-1 and -2, prostaglandin E2 receptor, IL-15 and TGF-type II receptor for which expression increased.[10] Notably, OPN expression from uterine glands increased 12-fold at the receptive phase in women[10] and up to 60-fold during pregnancy in rats,[11] suggesting a direct role in embryo-uterine interactions. Similar microarray studies are addressing uterine gene expression in early bovine pregnancy.[12]

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