Abstract
BackgroundCommercial swine breeds in North America undergo two waves of spontaneous fetal loss; one during peri-attachment and another during mid-gestation. Although an exact mechanism for this loss is not known, deficits in vasculature at the attachment sites appear to be a major cause. We hypothesized that a balance between pro-angiogenic and anti-angiogenic factors is needed at the maternal-fetal interface for successful conceptus development. Six selected members of the pro-angiogenic fibroblast growth factor (FGF) and platelet derived growth factor (PDGF) families and anti-angiogenic factor thrombospondin-1 (TSP-1) and its receptor CD36 were quantified and localized at the porcine maternal-fetal interface at early and midgestation time points.MethodsMesometrial endometrium was collected from non-pregnant gilts (n = 8). Endometrial and chorioallantoic membrane samples were collected from healthy and arresting conceptus attachment sites at gestation day (gd) 20 (n = 8) and gd 50 (n = 8). At gd20 arresting conceptus attachment sites were distinguished by decreased vasculature of the placental membranes and decreased conceptus size. At gd50 arresting conceptuses attachment sites were identified by smaller conceptus length and weight measurements. Quantitative real time PCR was used to determine relative transcript levels of genes of interest, and cellular localization was determined by immunohistochemistry in paraffin embedded endometrial sections.ResultsAt gd20, endometrial samples from arresting conceptuses had elevated transcripts for bFGF, and PDGF-bb than healthy sites (p < 0.05). At gd50, bFGF, FGFR2, and CD36 were more abundant at arresting than at healthy conceptus attachment sites (p < 0.05). Chorioallantoic membrane from arresting conceptus attachment sites at gd20 had elevated transcripts for bFGF, FGFR1, FGFR2 and CD36 compared with healthy sites (p < 0.05). FGFR2 transcripts were more abundant in chorioallantoic membrane from arresting conceptuses at gd 50 (p < 0.05). Immunohistochemical localization of selected pro- and anti-angiogenic factors and receptors revealed their abundance in the luminal epithelium, uterine glands and perivascular areas of endometrium at gd20 and gd50.ConclusionsWe provide comprehensive analysis of pro and anti-angiogenic factors at the porcine maternal fetal interface during early and mid-pregnancy. At mRNA levels, the majority of pro-angiogenic factors investigated were elevated at the sites of fetal arrest. These observations contrast with our previous findings of decreased Vascular Endothelial Growth Factor (VEGF) family members at arresting sites, and suggest that the bFGF family functions as a compensatory survival mechanism when major angiogenic proteins are decreasing at the sites of fetal arrest.
Highlights
Commercial swine breeds in North America undergo two waves of spontaneous fetal loss; one during peri-attachment and another during mid-gestation
Expression of Basic Fibroblast Growth Factor (bFGF), FGFR1, FGFR2 mRNAs level and immunolocalization Basic fibroblast growth factor, FGFR1, and FGFR2 were transcribed in non-pregnant endometrium as well as endometrium and chorioallantoic membrane at gd20 and 50 (Figure 1)
Transcripts of bFGF were higher in endometrium from arresting conceptus attachment sites compared to tissue from healthy sites at both gd20, and gd50 (p < 0.05) (Figure 1A)
Summary
Commercial swine breeds in North America undergo two waves of spontaneous fetal loss; one during peri-attachment and another during mid-gestation. Exact mechanisms for the fetal loss are still unknown, angiogenesis appears to be crucial in successful development of conceptuses through gestation. Investigations of the porcine maternal-fetal interface at time points representative of the periattachment [3,4,7] and mid-gestational [7] stages of conceptus loss showed that conceptuses undergoing growth arrest had decreased endometrial vasculature compared to their healthy counterparts. There was no direct evidence that the arresting conceptuses identified at early or mid-gestation will be lost later during gestation, our studies provided first evidence [3,4,7] that dysregulation in angiogenesis at the maternal-fetal interface is a prime cause leading to growth arrest of developing conceptuses. Given that angiogenesis is a complex process which is regulated through a number of alternate pathways, we extended our investigations of the maternal-fetal interface in relation to pregnancy success or failure
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