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

Dev Biol. 2021 Sep;477:70-84. doi: 10.1016/j.ydbio.2021.05.008. Epub 2021 May 18.

Abstract

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.

Keywords: CXCL12; CXCR4; Coronary development; Gain-of-function; Lymphatic vessel development; Vascular development.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Blood Vessels / anatomy & histology
  • Blood Vessels / embryology*
  • Endothelial Cells / metabolism
  • Endothelial Cells / physiology*
  • Gain of Function Mutation
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Physiologic / physiology*
  • Receptors, CXCR4 / biosynthesis
  • Receptors, CXCR4 / physiology*
  • Vascular Remodeling / physiology

Substances

  • CXCR4 protein, mouse
  • Receptors, CXCR4