Angiogenic role of orexin-A via the activation of extracellular signal-regulated kinase in endothelial cells.
Orexin-A, a neuropeptide originally discovered in the hypothalamus, is found in peripheral organs, as well as in the central nervous system, and is involved in the regulation of food intake, energy homeostasis, and cardiovascular functions. In this study, we report that orexin-A induces invivo neovascularization in a mouse Matrigel plug and ex vivo sprouting of endothelial cells in rat aortic rings. We also show that orexin-A increases migration and tube formation in human umbilical vein endothelial cells (HUVECs), and this effect is mediated by orexin receptors on endothelial cells. Moreover, orexin-A activates the extracellular signal-regulated kinase 1/2 (ERK1/2) in HUVECs, which is closely linked to angiogenic responses. The inhibition of ERK activation significantly suppresses orexin-A-stimulated endothelial angiogenesis. Taken together, our results indicate that orexin-A functions as a new proangiogenic peptide and requires MEK/ERK-dependent pathway for its angiogenic actions. These results suggest orexin-A and its receptor may act as important modulators of angiogenesis under pathophysiological conditions.
School of Dentistry, Pusan National University, Yangsan 626-770, South Korea.
Mi-Kyoung
MK
Kim
Hyun-Joo
HJ
Park
Su-Ryun
SR
Kim
Yoon Kyung
YK
Choi
Hwa Kyoung
HK
Shin
Jae-Hoon
JH
Jeon
Hye-Ock
HO
Jang
Il
I
Yun
Soo-Kyung
SK
Bae
Moon-Kyoung
MK
Bae
D000818:Animals; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009479:Neuropeptides / Q000494:pharmacology / Q000502:physiology*; D000068797:Orexins; D051381:Rats
C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3