Platelet involvement is thought to be due to: release of growth factors or platelet-vessel interactions. Platelets contain agranules, dense granules, and lysosomes. The a-granule content includes both pro- and anti-angiogenic growth factors that are important regulators of some tumour growth. Platelet releasate has been linked with in vitro and in vivo angiogenesis, involving neuropeptide Y and the angiopoietin pathway. The mechanism of growth factor Dabrafenib sequestration is unclear, but may involve endocytosis of circulating vascular endothelial growth factor or enhanced VEGF production by megakaryocytes. There has been an interest in nonhaemostatic roles for platelets since the discovery that platelet depletion prevents growth of metastases. Patients with cancers and inflammatory disorders that induce pathological angiogenesis demonstrate higher platelet levels of growth factors, including VEGF. It is known that the higher VEGF levels parallels tumour progression, and platelets are activated in the circulation of such individuals. Lystbg mice lacking dense granules and lysosomes demonstrate normal inflammatory angiogenesis, suggesting a role for granule release. Interestingly, pro-angiogenic and anti-angiogenic factors may be selectively released from platelets. Evidence supporting the need for platelet adhesion includes unaffected in vitro endothelial tube formation in Matrigel by the addition of platelet secretate, which includes a-granule secretions, that is enhanced with the physical presence of platelets. Also, platelet adhesion onto tumour endothelium is accompanied by VEGF release, and significantly more platelets have been observed adherent to angiogenic vessels compared to mature vasculature with intravital microscopy studies of dorsal skinfold chambers, supporting a role for platelet-vessel interactions. Whether platelets interact with endothelium or subendothelial structures remains unclear. While platelets bind subendothelial collagen after vessel injury during thrombosis, no evidence exists for a functional role of such interactions in physiological angiogenesis, nor for circulating platelet activation. Mice lacking GPVI, of central importance to direct platelet activation, demonstrate inflammatory angiogenesis in response to subcutaneous Matrigel implantation no differently from controls. This suggests that intact collagen binding properties may not be required for angiogenesis to occur in vivo. Thus, platelet adhesion to endothelium may lead to angiogenesis as a result of releasate from activated platelets, but that secretion of proangiogenic factors may also occur without adhesion. For example, quiescent platelets may more effectively stimulate wound healing compared with activated platelets, possibly by enhancing fibroblast differentiation. We therefore sought to identify a role for platelets using two in vivo models of physiological angiogenesis, sprouting and splitting forms of capillary growth.