Lymphangiogenesis is the formation of new lymphatic vessels from pre-existing ones. In adulthood, this process appears almost exclusively during pathologies such as cancer, inflammation and lymphedema. Lymphangiogenesis can also have beneficial effects in other pathologies such as myocardial infarction. Processes guiding lymphangiogenesis remain largely unknown in comparison to those governing angiogenesis, the formation of new blood vessels. Adenosine is a purine nucleoside mainly produced through ATP and AMP metabolism. Adenosine is constitutively present in the whole body but its concentration can increase in case of stress or hypoxia for example. Adenosine intervenes in different pathologies. For example, it can be beneficial during myocardial infarction. Recent studies show that tumor associated macrophages secrete large quantities of adenosine. Adenosine can also promote angiogenesis. The impact of adenosine on lymphangiogenesis is poorly understood except for a vasodilatation effect. During this work, we studied the effects of adenosine on lymphangiogenesis. For this study, we used different in vitro models to study lymphangiogenesis. We used cell proliferation assays, migration, tubulogenesis and spheroid model assay. All these models showed inhibition of lymphangiogenesis by adenosine in vitro. Two study models were also used in vivo. The first one is an ear collagen implant model in mice; the second one is the use of an adenoviral vector allowing an adenosine over-expression in mice. In these two models, adenosine increased lymphangiogenesis in vivo. This increase seems linked to an increase of number of macrophages at sites where adenosine production is increased. In both in vitro models, we have shown that this increase of lymphangiogenesis was mediated through the A2b adenosine receptor and was accompanied by an increase of VEGF-A secretion by macrophages. To conclude, our work allows a better understanding of the effects of adenosine on lymphangiogenesis. These results contribute to characterize the mechanisms leading to the formation of metastasis and to could lead to new therapeutic targets for the regulation of lymphangiogenesis.
|8 Jan 2015
|Published - 8 Jan 2015