期刊
BLOOD
卷 118, 期 3, 页码 775-785出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2010-09-306001
关键词
-
类别
资金
- Ministry of Education, Science, Sports, and Culture of Japan
- Ministry of Health, Labor, and Welfare of Japan
- Project for Realization of Regenerative Medicine
- Japan Society for the Promotion of Science
- Grants-in-Aid for Scientific Research [23659415, 21390239, 23791731, 23122509] Funding Source: KAKEN
The opioid system (opioid peptides and receptors) regulates a variety of neurophysiologic functions, including pain control. Here we show novel roles of the kappa opioid system in vascular development. Previously, we revealed that cAMP/protein kinaseA(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. (Blood. 2011;118(3):775-785)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据