APJ Regulates Parallel Alignment of Arteries and Veins in the Skin

Dev Cell. 2015 May 4;33(3):247-59. doi: 10.1016/j.devcel.2015.02.024. Epub 2015 Apr 23.

Abstract

Molecular pathways regulating the development of arterial and venous endothelial cells (ECs) are now well established, but control of parallel arterial-venous alignment is unclear. Here we report that arterial-venous alignment in the skin is determined by apelin receptor (APJ) expression in venous ECs. One of the activators of APJ is apelin. We found that apelin is produced by arterial ECs during embryogenesis, induces chemotaxis of venous ECs, and promotes the production of secreted Frizzled-related protein 1 (sFRP1) by APJ(+) ECs. sFRP1 stimulates matrix metalloproteinase production by Ly6B.2(+) neutrophil-like cells located between the arteries and veins, resulting in remodeling of extracellular matrices to support venous displacement. Moreover, using apelin- or APJ-deficient mice, which exhibit arterial-venous disorganization, we found that arterial-venous alignment is involved in thermoregulation, possibly by regulating countercurrent heat exchange. We hypothesize that the evolution of parallel juxtapositional arterial-venous alignment was an adaptation to reduce body heat loss.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipokines
  • Animals
  • Apelin
  • Apelin Receptors
  • Arteries / metabolism*
  • Arteries / pathology
  • Body Temperature Regulation / physiology
  • Endothelial Cells / metabolism
  • Endothelium, Vascular / metabolism
  • Glycoproteins / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Neovascularization, Physiologic / physiology
  • Receptors, G-Protein-Coupled / metabolism*
  • Skin / blood supply*
  • Skin / metabolism
  • Veins / metabolism*

Substances

  • APLN protein, human
  • APLNR protein, human
  • Adipokines
  • Apelin
  • Apelin Receptors
  • Apln protein, mouse
  • Aplnr protein, mouse
  • Glycoproteins
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Receptors, G-Protein-Coupled
  • WD repeat containing planar cell polarity effector