Search

Vascular endothelial growth factor A (VEGF-A) is a major contributor to physiological and pathological angiogenesis in the body. VEGF-A exists as several isoforms varying significantly in their function and angiogenic potential due to their different exon compositions. VEGF111, the most recently discovered isoform, has unique characteristics, being the only isoform resistant to proteolytic cleavage by plasmin and is also freely diffusable. This thesis aimed to investigate the role and regulation of these isoforms in three major conditions, ovarian hyperstimulation (OH), endometriosis, and tumour invasion metastasis. There are currently limited studies available analysing the expression of VEGF-A isoforms in these conditions and how this may impact angiogenesis. This is especially true for VEGF111 where research is greatly limited, and until now, it has not been identified in any human tissue. Thus, we hypothesised that the expression of VEGF111 and the other VEGF-A isoforms may be upregulated and/or disturbed in these conditions and contribute to their progression. This study aimed to advance our current understanding behind VEGF111 mediated angiogenesis and determine if VEGF111 plays a significant role in human disease. While VEGF111 is present in the rat uterus, during early pregnancy its levels fall below the limit of detection of conventional qPCR assays. But, analysis of the more common isoforms revealed the downregulation of VEGF188 specifically at the time of uterine receptivity following OH procedures in the rat. This downregulation was also associated with abnormal and enlarged vessels in the OH uterus at this time. Our studies on the human endometrium were more promising and for the first time we have identified the natural expression of VEGF111 in human tissue, specifically within the human endometrium. Furthermore, we showed that these levels of VEGF111, as well as the other VEGF-A isoforms, are upregulated during menstruation in women with endometriosis, highlighting the importance of specifically studying the menstrual phase in endometriosis. To investigate the angiogenic effects of VEGF111 we analysed the effects of VEGF-A isoforms in a three-dimensional cell culture model and confirmed that VEGF111 is highly angiogenic compared to the better known isoforms VEGF121 and VEGF165.