Background: Inadequate foetal growth cannot be remedied postnatally, leading to severe consequences for neonatal and adult development. Furthermore, sexual dimorphism in placental development has been suggested in humans although this remains poorly investigated in the pig. Hypotheses: Intrauterine Growth Restriction (IUGR) occurs due to aberrant conceptus attachment, which leads to alterations in angiogenesis and vascularity of the feto-maternal interface. Altered gene expression and vascularity will be observed at the feto-maternal interface in male foetuses compared to female foetuses. Increased apoptosis and decreased proliferation will be observed in the feto-maternal interface associated with the lightest foetuses compared to the closest to mean litter weight (CTMLW) foetuses. Aims: This thesis aimed to investigate the association between foetal size and sex and: integrin signalling; apoptotic and proliferation pathways; umbilical arterial (UA) blood flow; and angiogenesis and vascularity at the feto-maternal interface. This was performed by the collection of placental and endometrial samples associated with conceptuses or foetuses of different size (lightest and CTMLW) and sex at gestational day (GD) 18, 30, 45, 60 and 90. Conclusion This thesis has presented novel findings of associations between foetal size and sex, and placental and endometrial integrin signalling, apoptosis and proliferation, and angiogenesis and vascularity. Currently, this is the first suggestion in the literature that foetal size, and more intriguingly foetal sex, may have a strong influence on the activity of the endometrium. The mechanisms behind these findings warrant further investigation. Switches in the direction of differences at the feto-maternal interface between foetuses of different size were observed throughout gestation, notably between GD45 and 60, highlighting the dynamic nature of the feto-maternal interface and suggesting this as a potential window that could be manipulated by the industry to attempt to rescue the postnatal phenotype of IUGR piglets.

<p>Formation of blood vessels occurs through two processes: vasculogenesis and angiogenesis, which are regulated by various growth factors such as vascular endothelial growth factor, fibroblast growth factor and platelet-derived growth factor. The present study was carried out in order to investigate the roles of the Shb and Cbl proteins in growth factor-mediated signal transduction and blood vessel formation. Shb was found to be involved in NGF-stimulated Rap1 signaling in PC12 cells by forming a complex with CrkII and a 130-135 kDa protein. The Rap1 signaling pathway contributed to NGF-dependent neurite outgrowth. In immortomouse brain endothelial (IBE) cells, Shb increased cell spreading, migration and cytoskeletal rearrangements. Such effects may partly be due to altered Rap1 activation in Shb overexpressing IBE cells. Shb was required for tubular morphogenesis in collagen gels in the presence of FGF-2. In embryoid bodies (EBs) derived from murine embryonic stem cells, Shb up-regulated both VEGFR2 and Tal1 expression at early stages of EB development and thus promoted blood vessel formation both in the absence and in the presence of growth factors. In IBE cells, Cbl positively regulated FGF-2 signaling and increased cell proliferation. Mutation of RING finger alone did not affect blood vessel formation in EBs. However, EBs overexpressing the oncogenic form Cbl 70Z, which had a deletion of the linker region and the first cysteine of the RING finger, exhibited intense CD31 positive sheet-like staining and blood vessel. The results suggested that Cbl had dual roles in endothelial cells: it promoted FGF-2-induced proliferation whereas down-regulated proliferation of endothelial progenitor cells.</p><p>The present work suggests that Shb and Cbl play a crucial role in cell differentiation and blood vessel formation.</p>

Formation of blood vessels occurs through two processes: vasculogenesis and angiogenesis, which are regulated by various growth factors such as vascular endothelial growth factor, fibroblast growth factor and platelet-derived growth factor. The present study was carried out in order to investigate the roles of the Shb and Cbl proteins in growth factor-mediated signal transduction and blood vessel formation. Shb was found to be involved in NGF-stimulated Rap1 signaling in PC12 cells by forming a complex with CrkII and a 130-135 kDa protein. The Rap1 signaling pathway contributed to NGF-dependent neurite outgrowth. In immortomouse brain endothelial (IBE) cells, Shb increased cell spreading, migration and cytoskeletal rearrangements. Such effects may partly be due to altered Rap1 activation in Shb overexpressing IBE cells. Shb was required for tubular morphogenesis in collagen gels in the presence of FGF-2. In embryoid bodies (EBs) derived from murine embryonic stem cells, Shb up-regulated both VEGFR2 and Tal1 expression at early stages of EB development and thus promoted blood vessel formation both in the absence and in the presence of growth factors. In IBE cells, Cbl positively regulated FGF-2 signaling and increased cell proliferation. Mutation of RING finger alone did not affect blood vessel formation in EBs. However, EBs overexpressing the oncogenic form Cbl 70Z, which had a deletion of the linker region and the first cysteine of the RING finger, exhibited intense CD31 positive sheet-like staining and blood vessel. The results suggested that Cbl had dual roles in endothelial cells: it promoted FGF-2-induced proliferation whereas down-regulated proliferation of endothelial progenitor cells. The present work suggests that Shb and Cbl play a crucial role in cell differentiation and blood vessel formation.