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For this purpose, bone marrow transplant experiments were performed where female wild-type recipient mice were lethally irradiated to ablate all endogenous bone marrow and immediately given intravenous injections of whole bone marrow cell suspensions from either female ��6fl/fl-Tie1Cre? or ��6fl/fl-Tie1Cre+ mice. Six weeks post-transplant, the mice were then injected subcutaneously with B16F0 melanoma cells. The resultant tumour sizes and blood vessel densities were similar in both transplanted groups, suggesting that any potential loss of ��6-integrin in the haematopoietic compartment of the ��6fl/fl-Tie1Cre+ mice was not sufficient to affect tumour size or tumour angiogenesis (Supporting information, Supplementary Figures 2a and 2b). As expected, overall tumour size was reduced in these experiments when compared with non-transplanted experiments in Figure 3, since irradiation is known to reduce tumour growth. Efficient GUCY1B3 bone marrow constitution was illustrated by the presence of male bone marrow-derived Y-chromosome by in situ hybridization in bone marrow smears from female mice transplanted with male bone marrow and control male bone marrow (Supporting information, Supplementary Figure 2c). Therefore, although ��6-integrin may play a role in bone marrow-derived angiogenesis, this is not likely in the case KD025 cell line of the Tie1Cre mouse model that we have used. Thus, we concentrated our investigations on the role of ��6-integrin deficiency in endothelial cells. Vascular endothelial growth factor (VEGF) is a major pro-angiogenic factor and plays a significant role in the growth of tumours. To test whether endothelial ��6-integrin deficiency specifically affected VEGF-stimulated angiogenesis in vivo, sterile synthetic sponges were implanted subcutaneously into the flanks of adult ��6fl/fl-Tie1Cre? and ��6fl/fl-Tie1Cre+ mice and sponges were injected with either PBS or VEGF (10 ng/ml) every 2 days, over a 14-day period. Histological analysis of laminin-positive blood vessel density within the sponges revealed that endothelial ��6-integrin deficiency in ��6fl/fl-Tie1Cre+ mice resulted in an enhanced angiogenic response to VEGF compared with ��6fl/fl-Tie1Cre? controls. No significant difference was observed when the mean blood vessel density of PBS-treated sponges was compared between genotypes (**p epigenetics inhibitor Figure 4a). This enhanced response to VEGF was confirmed ex vivo by the significantly enhanced VEGF-mediated microvessel sprouting from cultured ��6fl/fl-Tie1Cre+ aortic rings when compared with ��6fl/fl-Tie1Cre? controls (**p