| First Author | Yamamizu K | Year | 2011 |
| Journal | Blood | Volume | 118 |
| Issue | 3 | Pages | 775-85 |
| PubMed ID | 21460241 | Mgi Jnum | J:174909 |
| Mgi Id | MGI:5141394 | Doi | 10.1182/blood-2010-09-306001 |
| Citation | Yamamizu K, et al. (2011) The {kappa} opioid system regulates endothelial cell differentiation and pathfinding in vascular development. Blood 118(3):775-85 |
| abstractText | 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 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. |
