Involvement of molecules related to angiogenesis, proteolysis and apoptosis in implantation in rhesus monkey and mouse.
We have established the well-defined cycling, pseudo-pregnant and pregnant rhesus monkey models, and used these to analyze expression of the common molecules specifically related to angiogenesis, apoptosis or proteolysis, such as vascular endothelial growth factor (VEGF) and its receptors KDR, flt-1, flt-4 and flk-1, basic fibroblast growth factor (bFGF) and its receptors Flg, transforming growth factor-alpha and beta1 (TGF-a/beta1), and TGF-beta1 receptor type I (TbetaR-I) and type II (TbetaR-II), as well as steroidogenic acute regulatory protein (StAR), tissue type plasminogen activator/urokinase plasminogen activator/plasminogen activator inhibitor type 1 (tPA/uPA/PAI-1) and matrix matalloproteinase type 1, -3/tissue inhibitor matalloproteinase type 1, -2, -3 (MMP-1, -3/TIMP-1, -2, -3), Fas/FasL, BcL-2/Bax, in the corpus luteum (CL), in the functional layer of the endometrium and in the materno-fetal boundary of the implantation site. We have demonstrated that: expression of these molecules in the monkey CL, endometrium and materno-fetal boundary of the implantation site is correlated well with CL functional and vascular development and with the processes involved in the establishment of the implantation window as well as with the early stages of placentation. A coordinated increase in tPA and its inhibitor PAI-1 expression in the monkey and rat CL may be instrumental in initiating luteal regression in both species, and correlated well with the timing of the closure of the implantation window, whereas high uPA activity in the CL is important for the early formation of the CL and for maintaining its function which is closely correlated to the period of establishment of the implantation window. Apoptosis, proteolysis and angiogenesis occur in the CL and in the endometrium during the time of establishment of the implantation window, as well as in the materno-fetal boundary of the implantation site at the early stages of placentation. It seems that these processes occur in these tissues in a coordinated and time- and cell-dependent manner, and are reliant on each other. Based on these observations, we have designed experiments to test the actions of some related available compounds on mouse implantation, used alone or in combination. The preliminary data showed that the compounds which could effectively affect apoptosis, angiogenesis or proteolysis in the implantation site were capable of effectively inhibiting implantation by acting on the endometrium and/or on the CL. Furthermore, the combined use of these compounds produced an obvious additive effect on inhibiting implantation. This finding suggested this may be a good approach for developing an anti-implantation agent.
Liu
Yi-Xun
YX
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, China. liuyx@ioz.ac.cn
Gao
Fei
F
Wei
Peng
P
Chen
Xin-Lei
XL
Gao
Hong-Juan
HJ
Zou
Ru-Jin
RJ
Siao
Li-Juan
LJ
Xu
Fu-Hua
FH
Feng
Qing
Q
Liu
Kui
K
Hu
Zhao-Yuan
ZY
D000818:Animals; D017209:Apoptosis; D003338:Corpus Luteum / Q000378:metabolism*; D010064:Embryo Implantation; D004717:Endometrium / Q000378:metabolism*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D000091344:Filaggrin Proteins; D006801:Humans; D003341:Luteolysis / Q000378:metabolism; D008253:Macaca mulatta; D051379:Mice; D023421:Models, Animal; D018919:Neovascularization, Physiologic; D011247:Pregnancy / Q000378:metabolism*; D011270:Pregnancy, Animal / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015291:Transforming Growth Factors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D017468:Receptors, Fibroblast Growth Factor; D018125:Receptors, Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D015291:Transforming Growth Factors; D040262:Receptors, Vascular Endothelial Growth Factor