The C-type lectin CD93 in physiological and pathological angiogenesis

Formation of blood vessels is required for development, growth and healing. Although quiescent, endothelial cells (ECs) store a potent proliferative and invasive potential that, upon the appropriate stimuli, is unleashed and gives rise to neovascularization phenomena. Disease progression of cancer and neovascular age-related macular degeneration (nAMD) strongly depends on angiogenesis. In cancer, tumor cells are able to stimulate ECs to become angiogenic and form new blood vessels that allow them to fulfill their tendency to grow and escape the site of the primary tumor. In nAMD, instead, inflammation and drusen deposition induce a strong damage to the retinal pigment epithelium (RPE), which in response to the damage triggers abnormal vessel formation that directly causes disease progression and consequent vision loss. In light of the role that angiogenesis plays in these diseases, targeting blood vessels with anti-angiogenic drugs has always been an appealing concept. However, due to the partial failure of anti-angiogenic therapies in the treatment of such diseases, it has become crucial to find alternative strategies that rely on targeting new molecules in a way to show great efficacy with minimal toxic effects. CD93 is a transmembrane glycoprotein that has been shown to have a prevalent role in controlling EC function, such as cell adhesion and migration. In this work, we investigated the molecular pathways behind the function of CD93 as regulator of EC adhesion and migration, showing that CD93 regulates actin dynamics via the small GTPases Rac1, Cdc42 and RhoA in a signaling axis triggered by its phosphorylation and interaction with Cbl phosphorylated on tyrosine 774. We also gained insights on the functional transport of CD93 during adhesion and migration, demonstrating that it is regulated by both its cytoplasmic domain and the Rab5C-