Effect of norepinephrine on RhoA, MAP kinase, proliferation and VEGF expression in human umbilical vein endothelial cells.
Norepinephrine is a well known major vasoconstricting factor. Recent reports suggest that norepinephrine, in addition to acting as a vasoconstricting factor, may also play several additional roles in endothelial cells. These include: 1] induction of NO release. It has been demonstrated that a small GTP-binding protein, Rho, and its downstream effecter, Rho kinase (ROCK), negatively regulate endothelial nitric oxide synthase (eNOS) production. However, it is not known whether ROCK is directly involved in norepinephrine-induced NO release. 2] Norepinephrine is reported to induce a mitogenic effect, but whether MAPKs are involved in this process is unknown. 3] Recently, we demonstrated an increase in vascular endothelial growth factor (VEGF) mRNA/protein expression in human pheochromocytoma tissue in comparison to normal adrenomedullary tissue. Thus, it is reasonable to speculate that norepinephrine may stimulate the level of VEGF mRNA. The aim of the present study was to clarify the role of norepinephrine and related endothelial adrenoceptor systems in various pathophysiological conditions, such as hypertension and in particular pheochromocytoma, using human umbilical vein endothelial cells (HUVEC). Norepinephrine-induced RhoA attenuation, through cAMP/protein kinase A (PKA) activation coupled with beta-adrenoceptors, may lead to eNOS activation in acute conditions. Norepinephrine stimulates the production of VEGF mRNA through cAMP/PKA activation coupled with beta-adrenoceptors. Norepinephrine stimulates a mitogenic effect through ERK activation coupled with the alpha(1)-adrenoceptor. In conclusion, norepinephrine stimulates eNOS activity via RhoA attenuation, VEGF mRNA synthesis and mitogenic activity in endothelial cells. We propose that an excess of norepinephrine can lead to endothelial dysfunction due to these aforementioned processes.
Seya
Yumi
Y
Department of Clinical Pathology, University of Tsukuba (Institute of Clinical Medicine), Molecular Laboratory Medicine, Graduate School of Comprehensive Human Sciences, 1-1-1 Tennoudai, Tsukuba, 305-8575, Japan.
Fukuda
Toshiyuki
T
Isobe
Kazumasa
K
Kawakami
Yasushi
Y
Takekoshi
Kazuhiro
K
D015153:Blotting, Western; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D009638:Norepinephrine / Q000494:pharmacology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis; D011941:Receptors, Adrenergic / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013566:Sympathomimetics / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D020742:rhoA GTP-Binding Protein / Q000096:biosynthesis*
D012333:RNA, Messenger; D011941:Receptors, Adrenergic; D013566:Sympathomimetics; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III; D020928:Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein; D009638:Norepinephrine