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- The efects of low-dose ionizing radiation on angiogenesisPublication . Vala, Inês Sofia; Constantino, Susana; Zilhão, Rita, 1959-Angiogenesis is the formation of new blood vessels from pre‐existing ones. This process is regulated by a balance between pro‐ and anti‐angiogenic molecules and is derailed in various diseases, such as cancer. Radiotherapy is a commonly‐used treatment for cancer. However, recent studies suggest that ionizing radiation (IR) doses delivered inside the tumor target volume during fractionated radiotherapy can stimulate invasion and metastasis through effects on cancer cells but also on other elements of the microenvironment. Furthermore, radiotherapy results also in the delivery of doses lower that the therapeutic ones to the tissues surrounding the tumor area, and the biological effects of these low IR doses remain largely undetermined. Our overall goal was to investigate the effects of these low IR doses on angiogenesis, and consequently in tumor progression and metastasis. We showed that low‐dose IR induces an angiogenic response both in vitro and in vivo. Doses equal or lower than 0.8 Gy promote endothelial cell migration without causing cell cycle arrest or apoptosis, activate vascular growth factor (VEGF) receptor‐2 and upregulate the expression of VEGF. In zebrafish, low‐dose IR accelerates sprouting angiogenesis during development and enhances angiogenesis during regeneration. In mice, we showed that low‐dose IR promotes angiogenesis resulting in accelerated tumor growth and metastasis formation in a VEGFR‐dependent manner. Additionally, we demonstrated that low‐dose IR modulates the gene expression of molecular mediators involved in the angiogenic response. Our observations provide novel insights into the biological effects of low‐dose IR relevant to tumor biology, which may serve as basis for the prevention of possible tumorpromoting effects of current radiotherapy protocols. Therefore, according to our findings low‐dose IR induces angiogenesis in vivo but, there is no evidence that it produces therapeutic angiogenesis in ischemic disease patients. In the second part of this work we showed that low‐dose IR potentiates the pro‐angiogenic effect of vasoprost®, commonly used in the treatment of peripheral arterial disease treatment (PAD). Our results suggest that the combinatory use of both vasoprost® and low‐dose IR should be considered for future studies concerning its clinical therapeutic potential in pathologies such as PAD.