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Phosphatidylinositol transfer protein (PITP) has been identified as a key player in numerous signaling pathways relying on phosphatidylinositol (PI) metabolites.Its main function is to present PI to lipid kinases for localized production of phosphatidylinositol (4,5)-bisphosphate (PIP2), either as a signaling molecule (for example, in exocytosis) or as a substrate (for example, by phospholipases).We uncover a role of PITPx in the regulation of angiogenic signaling and remodeling of the vasculature.In zebrafish, PITPx is temporally and spatially expressed at the axial vasculature.Loss of PITPx disrupts the arterial-venous segregation process, resulting in compromised blood vessel integrity, manifested by shrunk PCV, defected lymphatic system and abnormal blood circulation at later stages.Furthermore, PITPx is required for endothelial cell survival and PCV progenitor cell migration from the precursor vessel.The compromised vascular integrity is traced to the abolished PITPx interaction with VEGFR2 complex and Rab proteins, which delays internalization and trafficking of VEGFR2.These results suggest that PITPx can regulate vascular integrity and angiogenesis, providing a new target for modulating vascular formation and function.