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7 August 2013 Transforming Growth Factor-Beta 1 (TGF-B1) Liberation from Its Latent Complex During Embryo Implantation and Its Regulation by Estradiol in Mouse
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Abstract

Transforming growth factor-beta (TGF-B) plays an important role in embryo implantation; however, TGF-B requires liberation from its inactive latent forms (i.e., large latent TGF-B complex [LLC] and small latent TGF-B complex [SLC]) to its biologically active (i.e., monomer or dimer) forms in order to act on its receptors (TGF-BRs), which in turn activate SMAD2/3. Activation of TGF-B1 from its latent complexes in the uterus is not yet deciphered. We investigated uterine latent TGF-B1 complex and its biologically active form during implantation, decidualization, and delayed implantation. Our study, utilizing nonreducing SDS-PAGE followed by Western blotting and immunoblotting with TGF-B1, LTBP1, and latency-associated peptide, showed the presence of LLC and SLC in the uterine extracellular matrix and plasma membranous protein fraction during stages of the implantation period. A biologically active form of TGF-B1 (∼17-kDa monomer) was highly elevated in the uterine plasma membranous compartment at the peri-implantation stage (implantation and nonimplantation sites). Administration of hydroxychloroquine (an inhibitor of pro-TGF-B processing) at the preimplantation stage was able to block the liberation of biologically active TGF-B1 from its latent complex at the postimplantation stage; as a consequence, the number of implantation sites was reduced at Day 5 (1000 h), as was the number of fetuses at Day 13. The inhibition of TGF-B1 showed reduced levels of phosphorylated SMAD3. Further, the delayed-implantation mouse model showed progesterone and estradiol coordination to release the active TGF-B1 form from its latent complex in the receptive endometrium. This study demonstrates the importance of liberation of biologically active TGF-B1 during the implantation period and its regulation by estradiol.

Vineet Kumar Maurya, Rajesh Kumar Jha, Vijay Kumar, Anubha Joshi, Sangappa Chadchan, Jasna Jagan Mohan, and Malini Laloraya "Transforming Growth Factor-Beta 1 (TGF-B1) Liberation from Its Latent Complex During Embryo Implantation and Its Regulation by Estradiol in Mouse," Biology of Reproduction 89(4), (7 August 2013). https://doi.org/10.1095/biolreprod.112.106542
Received: 27 November 2012; Accepted: 1 August 2013; Published: 7 August 2013
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