Blockade of the αvβ3 Integrin Adversely Affects Implantation in the Mouse1

Illera, M.; Cullinan, Emily B.; Gui, Yaoting; Li, Yuan; Beyler, Stan A.; Lessey, Bruce A.

doi:10.1095/biolreprod62.5.1285

Cited by 189 publications

(112 citation statements)

References 26 publications

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“…Fibronectin belongs to a member of ECM molecules identified at the conceptus-endometrium interface, which is capable of serving as a ligand for the receptor, integrin family. Fibronectin is also implicated in murine trophoblast outgrowth and adhesion processes, both of which could be blocked with RGD-containing peptides in vivo (39) and in vitro (40). The blocking with RGD peptides abolished the IP-10 stimulated adhesion activity of trophoblast cells to fibronectin, and EDTA, an inhibitor of integrin signaling, also abolished the adhesion activity.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Blastocyst Migration, Apposition, and Initial Adhesion by a Chemokine, Interferon γ-inducible Protein 10 kDa (IP-10), during Early Gestation

Nagaoka

Nojima

Watanabe³

et al. 2003

Journal of Biological Chemistry

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For a pregnancy to be established, initial apposition and adhesion of the blastocyst to maternal endometrium must occur in a coordinated manner; however, a key factor(s) that mediates the trophoblast cell migration and attachment to the apical surface of the endometrium has not been identified. In this study, we examined the effect of an endometrial chemokine, interferon-␥-inducible protein 10 kDa (IP-10), on conceptus migration to the endometrial epithelium. We first studied endometrial IP-10 mRNA expression, which was localized in the subepithelial stromal region, and detected the protein in the uterine flushing media during early pregnancy. Expression of IP-10 mRNA by the endometrium of cyclic animals was stimulated by the addition of a conceptus factor interferon-tau (IFN-). Immunofluorescent analysis revealed that IP-10 receptor, CXCR3, was localized in the trophoblast cells, to which biotinylated-recombinant caprine IP-10 (rcIP-10) bound. Chemotaxis assay indicated that rcIP-10 stimulated the migration of trophoblast cells, and the effects of rcIP-10 were neutralized by the pretreatment with an anti-IP-10 antibody. Adhesive activity of trophoblast cells to fibronectin was promoted by rcIP-10, and the effect was inhibited by the use of anti-IP-10 antibody. Further adhesion experiments demonstrated that binding of trophoblast cells to fibronectin was completely inhibited by a peptide of the Arg-Gly-Asp (RGD) sequence, which binds to integrins ␣ 5 ␤ 1 , ␣ V ␤ 1 , ␣ V ␤ 3 , and ␣ V ␤ 5 , whereas non-binding peptide containing Arg-Gly-Glu (RGE) had minimal effects. More importantly, rcIP-10 promoted the adhesion of trophoblast cells to primary cells isolated from endometrial epithelium. Furthermore, rcIP-10 stimulated the expression of integrin ␣ 5 , ␣ V , and ␤ 3 subunit mRNA in trophoblast cells. These findings suggest that endometrial IP-10 regulates the establishment of apical interactions between trophoblast and epithelial cells during early gestation.

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Section: Discussionmentioning

confidence: 99%

Regulation of Blastocyst Migration, Apposition, and Initial Adhesion by a Chemokine, Interferon γ-inducible Protein 10 kDa (IP-10), during Early Gestation

Nagaoka

Nojima

Watanabe³

et al. 2003

Journal of Biological Chemistry

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“…The central role of integrins in the implantation adhesion cascade is to bind ECM ligand(s) to cause cytoskeletal reorganization, stabilize adhesion, and mediate cell migration, proliferation and differentiation through numerous signaling intermediates (Giancotti & Ruoslahti 1999). Altered expression of integrins is correlated with several causes of infertility (Lessey 1998), null mutations of several integrins leads to peri-implantation lethality (Hynes 1996), and functional blockade of selected integrins reduces the number of implantation sites (Illera et al 2000). During the periimplantation period of pregnancy in ewes, integrin subunits a (v, 4, 5) and b (1, 3 and 5) are constitutively expressed on the apical surfaces of both conceptus trophoblast and endometrial LE .…”

Section: Integrinsmentioning

confidence: 99%

Implantation mechanisms: insights from the sheep

Spencer

Johnson²,

Bazer³

et al. 2004

Reproduction

284

232

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Implantation in all mammals involves shedding of the zona pellucida, followed by orientation, apposition, attachment and adhesion of the blastocyst to the endometrium. Endometrial invasion does not occur in domestic ruminants; thus, definitive implantation is achieved by adhesion of the mononuclear trophoblast cells to the endometrial lumenal epithelium (LE) and formation of syncytia by the fusion of trophoblast binucleate cells with the LE. This review highlights new information on mechanisms regulating the implantation cascade in sheep. The embryo enters the uterus on day 4 at the morula stage of development and then develops into a blastocyst by day 6. The blastocyst sheds the zona pellucida (day 8), elongates to a filamentous form (days 11-16), and adheres to the endometrial LE (day 16). Between days 14 and 16, the binucleate cells begin to differentiate in the trophoblast and subsequently migrate and fuse with the endometrial LE to form syncytia. Continuous exposure of the endometrium to progesterone in early pregnancy downregulates the progesterone receptors in the epithelia, a process which is associated with loss of the cell-surface mucin MUC1 and induction of several secreted adhesion proteins. Recurrent early pregnancy loss in the uterine gland knockout ewe model indicates that secretions of the endometrial epithelia have a physiologic role in blastocyst elongation and implantation. A number of endometrial proteins have been identified as potential regulators of blastocyst development and implantation in sheep, including glycosylated cell adhesion molecule 1 (GlyCAM-1), galectin-15, integrins and osteopontin. The epithelial derived secreted adhesion proteins (GlyCAM-1, galectin-15 and osteopontin) are expressed in a dynamic temporal and spatial manner and regulated by progesterone and/or interferon tau, which is the pregnancy recognition signal produced by the trophoblast during blastocyst elongation. The noninvasive and protracted nature of implantation in domestic animals provides valuable opportunities to investigate fundamental processes of implantation that are shared among all mammals. Understanding of the cellular and molecular signals that regulate uterine receptivity and implantation can be used to diagnose and identify causes of recurrent pregnancy loss and to improve pregnancy outcome in domestic animals and humans.

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“…Induced Spp1 in pregnant uterine epithelium result in peri-implantation lethality and failure of chorioallantoic membrane fusion, and functional blockade of av and b3 integrins in mice and rabbits reduces the number of implantation sites (Hynes 1996, Illera et al 2000. While a clear role for avb3 in mouse implantation has not been defined, it is possible that its ligation, perhaps to luminal Spp1, leads to apical translocation of a5b1 for stable conceptus attachment through fibronectin (Sutherland et al 1993, Wang et al 2000, Armant 2005.…”

Section: Spp1 At the Placental-endometrial Interfacementioning

confidence: 99%

Secreted phosphoprotein 1 (osteopontin) is expressed by stromal macrophages in cyclic and pregnant endometrium of mice, but is induced by estrogen in luminal epithelium during conceptus attachment for implantation

White

Burghardt²,

Hu³

et al. 2006

Reproduction

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Secreted phosphoprotein 1 (SPP1, osteopontin) is the most highly upregulated extracellular matrix/adhesion molecule/cytokine in the receptive phase human uterus, and Spp1 null mice manifest decreased pregnancy rates during mid-gestation as compared with wild-type counterparts. We hypothesize that Spp1 is required for proliferation, migration, survival, adhesion, and remodeling of cells at the conceptus-maternal interface. Our objective was to define the temporal/spatial distribution and steroid regulation of Spp1 in mouse uterus during estrous cycle and early gestation. In situ hybridization localized Spp1 to luminal epithelium (LE) and immune cells. LE expression was prominent at proestrus, decreased by estrus, and was nearly undetectable at diestrus. During pregnancy, Spp1 mRNA was not detected in LE until day 4.5 (day 1Zvaginal plug). Spp1-expressing immune cells were scattered within the endometrial stroma throughout the estrous cycle and early pregnancy. Immunoreactive Spp1 was prominent at the apical LE surface by day 4.5 of pregnancy and Spp1 protein was also co-localized with subsets of CD45-positive (leukocytes) and F4/80-positive (macrophages) cells. In ovariectomized mice, estrogen, but not progesterone, induced Spp1 mRNA, whereas estrogen plus progesterone did not induce Spp1 in LE. These results establish that estrogen regulates Spp1 in mouse LE and are the first to identify macrophages that produce Spp1 within the peri-implantation endometrium of any species. We suggest that Spp1 at the apical surface of LE provides a mechanism to bridge conceptus to LE during implantation, and that Spp1-positive macrophages within the stroma may be involved in uterine remodeling for conceptus invasion.

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Blockade of the αvβ3 Integrin Adversely Affects Implantation in the Mouse1

Cited by 189 publications

References 26 publications

Regulation of Blastocyst Migration, Apposition, and Initial Adhesion by a Chemokine, Interferon γ-inducible Protein 10 kDa (IP-10), during Early Gestation

Regulation of Blastocyst Migration, Apposition, and Initial Adhesion by a Chemokine, Interferon γ-inducible Protein 10 kDa (IP-10), during Early Gestation

Implantation mechanisms: insights from the sheep

Secreted phosphoprotein 1 (osteopontin) is expressed by stromal macrophages in cyclic and pregnant endometrium of mice, but is induced by estrogen in luminal epithelium during conceptus attachment for implantation

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