APJ Regulates Parallel Alignment of Arteries and Veins in the skin

• Published in: Developmental cell 2015-05, Vol.33 (3), p.247-259
• Main Authors: Kidoya, Hiroyasu, Naito, Hisamichi, Muramatasu, Fumitaka, Yamakawa, Daishi, Jia, Weizhen, Ikawa, Masahito, Sonobe, Takashi, Tsuchimochi, Hirotsugu, Shirai, Mikiyasu, Adams, Ralf H., Fukamizu, Akiyoshi, Takakura, Nobuyuki
• Format: Article
• Language: English
• Subjects: Adipokines; Animals; Apelin; Apelin Receptors; APJ; Arteries - metabolism; Arteries - pathology; artery; 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; Mice; Neovascularization, Physiologic - physiology; Receptors, G-Protein-Coupled - metabolism; Skin - blood supply; Skin - metabolism; thermoregulation; vein; Veins - metabolism
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2015.02.024

Molecular pathways regulating the development of arterial and venous endothelial cells (ECs) are now well-established, but control of parallel arterial-venous (A-V) 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. •Apelin or APJ mutant mice have abnormal arterial-venous (A-V) alignment•Apelin from arterial endothelial cells (ECs) induces chemotaxis of APJ+ venous ECs•Venous ECs induce neutrophil production of MMP9, allowing for EC migration•Mice with defective A-V alignment have defects in thermoregulation