Adrenomedullin reduces VEGF-induced endothelial adhesion molecules and adhesiveness through a phosphatidylinositol 3'-kinase pathway.
OBJECTIVE
In the initial phase of inflammation, vascular endothelial growth factor (VEGF) can act as a proinflammatory cytokine by inducing adhesion molecules that bind leukocytes to endothelial cells. Adrenomedullin (AM) is known to act as either a proinflammatory or an anti-inflammatory agent. In this study, we examined the effects of AM on adhesion molecule expression and leukocyte adhesiveness in VEGF-stimulated human umbilical vein endothelial cells.


RESULTS
When stimulated with VEGF, the mRNAs of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin were dose-dependently upregulated. AM inhibited the VEGF-induced protein and mRNA expression of ICAM-1, VCAM-1, and E-selectin. Phosphatidylinositol 3'-kinase inhibitor and a dominant-negative form of Akt significantly inhibited the suppressive effect of AM on VEGF-induced adhesion molecule expression. Thus, AM inhibits VEGF-stimulated ICAM-1 and VCAM-1 expression through a phosphatidylinositol 3'-kinase/Akt pathway. AM reduced VEGF-induced endothelial adhesiveness for leukocytes.


CONCLUSIONS
These results suggest that AM might have an anti-inflammatory role in controlling VEGF-induced adhesion molecule gene expression and adhesiveness toward leukocytes in endothelial cells.
Kim
Won
W
Department of Internal Medicine, Research Institute of Clinical Medicine, Chonbuk National University Medical School, Chonju, Republic of Korea.
Moon
Sang-Ok
SO
Lee
Sik
S
Sung
Mi Jeong
MJ
Kim
Sung Hoon
SH
Park
Sung Kwang
SK
D053607:Adrenomedullin; D002448:Cell Adhesion / Q000502:physiology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019040:E-Selectin / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism*; D004789:Enzyme Activation; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014657:Vasculitis / Q000503:physiopathology
D053607:Adrenomedullin; D015815:Cell Adhesion Molecules; D019040:E-Selectin; D018799:Intercellular Adhesion Molecule-1; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C467484:VEGFA protein, human; C494918:AKT1 protein, human