title: The κ opioid system regulates endothelial cell differentiation and pathfinding in vascular development.
abstract: The opioid system (opioid peptides and receptors) regulates a variety of neurophysiologic functions, including pain control. Here we show novel roles of the κ opioid system in vascular development. Previously, we revealed that cAMP/protein kinase A (PKA) signaling enhanced differentiation of vascular progenitors expressing VEGF receptor-2 (fetal liver kinase 1; Flk1) into endothelial cells (ECs) through dual up-regulation of Flk1 and Neuropilin1 (NRP1), which form a selective and sensitive VEGF(164) receptor. Kappa opioid receptor (KOR), an inhibitory G protein-coupled receptor, was highly expressed in embryonic stem cell-derived Flk1(+) vascular progenitors. The addition of KOR agonists to Flk1(+) vascular progenitors inhibited EC differentiation and 3-dimensional vascular formation. Activation of KOR decreased expression of Flk1 and NRP1 in vascular progenitors. The inhibitory effects of KOR were reversed by 8-bromoadenosine-3',5'-cAMP or a PKA agonist, N(6)-benzoyl-cAMP, indicating that KOR inhibits cAMP/PKA signaling. Furthermore, KOR-null or dynorphin (an endogenous KOR agonist)-null mice showed a significant increase in overall vascular formation and ectopic vascular invasion into somites at embryonic day -10.5. ECs in these null mice showed significant increase in Flk1 and NRP1, along with reciprocal decrease in plexinD1, which regulates vascular pathfinding. The opioid system is, thus, a new regulator of vascular development that simultaneously modifies 2 distinct vascular properties, EC differentiation and vascular pathfinding.
authors: Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors: Kohei
authors: K
authors: Yamamizu
authors: Sadayoshi
authors: S
authors: Furuta
authors: Shiori
authors: S
authors: Katayama
authors: Michiko
authors: M
authors: Narita
authors: Naoko
authors: N
authors: Kuzumaki
authors: Satoshi
authors: S
authors: Imai
authors: Hiroshi
authors: H
authors: Nagase
authors: Tsutomu
authors: T
authors: Suzuki
authors: Minoru
authors: M
authors: Narita
authors: Jun K
authors: JK
authors: Yamashita
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004399:Dynorphins / Q000235:genetics / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology* / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology; D039942:Neuropilin-1 / Q000378:metabolism; D011247:Pregnancy; D017473:Receptors, Opioid, kappa / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D017473:Receptors, Opioid, kappa; D039942:Neuropilin-1; D004399:Dynorphins; D000242:Cyclic AMP; D040301:Vascular Endothelial Growth Factor Receptor-2; D017868:Cyclic AMP-Dependent Protein Kinases