APJ Regulates Parallel Alignment of Arteries and Veins in the Skin.
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.
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Hiroyasu
H
Kidoya
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Hisamichi
H
Naito
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Fumitaka
F
Muramatsu
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Daishi
D
Yamakawa
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Weizhen
W
Jia
Animal Resource Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
Masahito
M
Ikawa
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Takashi
T
Sonobe
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Hirotsugu
H
Tsuchimochi
Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.
Mikiyasu
M
Shirai
Department of Tissue Morphogenesis, Max Planck Institute for Molecular Biomedicine, 48149 Muenster, Germany; Faculty of Medicine, University of Muenster, 48149 Muenster, Germany.
Ralf H
RH
Adams
Life Science Center, Tsukuba Advanced Research Alliance, The University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan.
Akiyoshi
A
Fukamizu
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, K's Gobancho, 7 Gobancho, Chiyoda-ku, Tokyo 102-0076, Japan. Electronic address: ntakaku@biken.osaka-u.ac.jp.
Nobuyuki
N
Takakura
D054392:Adipokines; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D001158:Arteries / Q000378:metabolism* / Q000473:pathology; D001833:Body Temperature Regulation / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018919:Neovascularization, Physiologic / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012867:Skin / Q000098:blood supply* / Q000378:metabolism; D014680:Veins / Q000378:metabolism*; D000099274:Frizzled-Related Proteins
D054392:Adipokines; D000073861:Apelin; D000075244:Apelin Receptors; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D043562:Receptors, G-Protein-Coupled; D000099274:Frizzled-Related Proteins; C115436:APLN protein, human; C104575:APLNR protein, human; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse