Isoform 111 of Vascular Endothelial Growth Factor (VEGF111) Improves Angiogenesis of Ovarian Tissue Xenotransplantation

Background. Cryopreservation of cortex ovarian tissue before anticancer therapy is a promising technique for fertility preservation mainly in children and young women. Ischemia in the early stage after ovarian graft causes massive follicle loss by apoptosis. VEGF(111) is a recently described vascular endothelial growth factor (VEGF) isoform that does not bind to the extracellular matrix, diffuses extensively, and is resistant to proteolysis. These properties confer a significantly higher angiogenic potential to VEGF(111) in comparison with the other VEGF isoforms. Methods. We evaluated the morphology of cryopreserved sheep ovarian cortex grafted in the presence or absence of VEGF(111). Ovarian cortex biopsies were embedded in type I collagen with or without VEGF(111) addition before transplantation to severe combined immunodeficient mice ovaries. Transplants were retrieved 3 days or 3 weeks later. Follicular density, vasculature network, hemoglobin content, and cell proliferation were analyzed. Results. Addition of VEGF(111) increased density of functional capillaries (P=0.01) 3 days after grafting. By double immunostaining of Ki-67 and von Willebrand factor, we demonstrated that proliferating endothelial cells were found in 83% of the VEGF(111) group compared with 33% in the control group (P=0.001). This angiostimulation was associated with a significant enhancement of hemoglobin content (P=0.03). Three weeks after transplantation, the number of primary follicles was significantly higher in VEGF(111) grafts (P=0.02). Conclusion. VEGF(111) accelerates blood vessel recruitment and functional angiogenesis and improves the viability of ovarian cortex by limiting ischemia and ovarian cortex damage.