Alterations in the spatiotemporal expression of the chemokine receptor CXCR4 in endothelial cells cause failure of hierarchical vascular branching

The C-X-C chemokine receptor CXCR4 and its ligand CXCL12 play an important role in organ-specific vascular branching morphogenesis. CXCR4 is preferentially expressed by arterial endothelial cells, and local secretion of CXCL12 determines the organotypic pattern of CXCR4⁺ arterial branching. Previous loss-of-function studies clearly demonstrated that CXCL12-CXCR4 signaling is necessary for proper arterial branching in the developing organs such as the skin and heart. To further understand the role of CXCL12-CXCR4 signaling in organ-specific vascular development, we generated a mouse model carrying the Cre recombinase-inducible Cxcr4 transgene. Endothelial cell-specific Cxcr4 gain-of-function embryos exhibited defective vascular remodeling and formation of a hierarchical vascular branching network in the developing skin and heart. Ectopic expression of CXCR4 in venous endothelial cells, but not in lymphatic endothelial cells, caused blood-filled, enlarged lymphatic vascular phenotypes, accompanied by edema. These data suggest that CXCR4 expression is tightly regulated in endothelial cells for appropriate vascular development in an organ-specific manner.