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Temporal and spatial expression of connective tissue growth factor (CCN2; CTGF) and transforming growth factor ß type 1 (TGF-ß1) at the utero–placental interface during early pregnancy in the pig

¹ Department of Surgery, Children's Research Institute, Children's Hospital and The Ohio State University, Columbus OH 43205, USA
² Department of Animal Science, Oklahoma Agricultural Experiment Station, Oklahoma State University, Stillwater OK 74078, USA

Correspondence to:
Dr D Brigstock, Children's Research Institute, 700 Children's Drive, Columbus OH43205, USA;
Brigstod{at}pediatrics.ohio-state.edu

ABSTRACT
Aims: To determine the localisation and distribution of connective tissue growth factor (CCN2; CTGF) and transforming growth factor ß type 1 (TGF-ß1) in uterine tissues from cycling and early pregnant pigs.

Methods: In situ hybridisation and immunohistochemistry were used to localise CCN2 (CTGF) or TGF-ß1 in uteri obtained from gilts on days 0, 5, 10, 12, 15, and 18 of the oestrous cycle or days 10, 12, 14, 16, 17, and 21 of gestation.

Results: In cycling animals, CCN2 (CTGF) mRNA and protein were abundant in luminal epithelial cells (LECs) and glandular epithelial cells (GECs), with lesser amounts in stromal fibroblasts and little or none in endothelial cells. A similar pattern of staining was seen up to day 10 of pregnancy, except that overall staining intensities for CCN2 (CTGF) mRNA or protein were higher and that stromal and endothelial cells were CCN2 (CTGF) positive. However, on days 12–17 there was a striking decrease in the amount of CCN2 (CTGF) in LECs at the utero–conceptus interface, which was associated with maternal stromal matrix reorganisation and the onset of subepithelial neovascularisation. This differential distribution of CCN2 (CTGF) was localised to those LECs that were in close proximity to or in apposition with trophoblast cells. This decrease in CCN2 (CTGF) staining was transient in nature and high amounts of CCN2 (CTGF) were again apparent in LECs on days 17–21, when endometrial neovascularisation and matrix remodelling were complete. The expression of uterine TGF-ß1 was comparable to that of CCN2 (CTGF) at most stages of the oestrous cycle or early pregnancy. Pre-elongation blastocysts recovered on day 10 were positive for both CCN2 (CTGF) and TGF-ß1 in the extra-embryonic trophectoderm, endoderm, and inner cell mass. On day 12, trophectoderm expressed low amounts of TGF-ß1 mRNA and non-detectable amounts of TGF-ß1 protein or CCN2 (CTGF) mRNA or protein. By days 17–21, the expression of both growth factors in the extra-embyronic/placental membranes increased and frequently exceeded that seen in LECs.

Conclusions: The pattern of CCN2 (CTGF) production during the initial attachment phase supports a role for this factor in stromal remodelling and neovascularisation, although alternative functions at later stages such as epithelial–epithelial interactions are also possible. In most major cell types in the uterus or utero–placental unit, CCN2 (CTGF) expression was highly correlated with that of TGF-ß₁, indicating that CCN2 (CTGF) may mediate some of the functions of TGF-ß in the reproductive tract during the oestrous cycle and pregnancy. The data further highlight epithelium as an important source of CCN2 (CTGF) in the regulation of uterine function.

Keywords: placenta; angiogenesis; extracellular matrix; epithelium; endothelium; CCN2 (CTGF)

Abbreviations: BSA, bovine serum albumin; CCN2/CTGF, connective tissue growth factor; ECM, extracellular matrix; FGF, fibroblast growth factor; GECs, glandular epithelial cells; LECs, luminal epithelial cells; PBS, phosphate buffered saline; TGF-ß1, transforming growth factor ß type 1

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