Transforming growth factor-beta 1 (TGF-B1) liberation from its latent complex during embryo implantation and its regulation by estradiol in mouse.
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.
Division of Endocrinology, CSIR-Central Drug Research Institute, Lucknow, India.
Vineet Kumar
VK
Maurya
Rajesh Kumar
RK
Jha
Vijay
V
Kumar
Anubha
A
Joshi
Sangappa
S
Chadchan
Jasna Jagan
JJ
Mohan
Malini
M
Laloraya
D000818:Animals; D003656:Decidua / Q000378:metabolism; D004195:Disease Models, Animal; D010064:Embryo Implantation; D010065:Embryo Implantation, Delayed; D004717:Endometrium / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D007247:Infertility, Female / Q000378:metabolism; D053779:Latent TGF-beta Binding Proteins / Q000378:metabolism; D051379:Mice; D010455:Peptides / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010929:Placentation; D011247:Pregnancy; D011374:Progesterone / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021382:Protein Sorting Signals; D051900:Smad3 Protein / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism
D053779:Latent TGF-beta Binding Proteins; C509033:Ltbp1 protein, mouse; D010455:Peptides; D011498:Protein Precursors; D021382:Protein Sorting Signals; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C472416:latency-associated propeptide, TGF-beta; D011374:Progesterone; D004958:Estradiol
TGF-B1 activation; decidualization; delayed implantation; embryo implantation; latent TGF-B1 complex; ovarian steroids