Vascular endothelial growth factor up-regulates expression of receptor activator of NF-κB (RANK) in endothelial cells. Concomitant increase of angiogenic responses to rank ligand

Jeong Ki Min, Young Myeong Kim, Young Mi Kim, Eok Cheon Kim, Yong Song Gho, Il Jun Kang, Soo Young Lee, Young Yun Kong, Young Guen Kwon

Research output: Contribution to journalArticle

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Abstract

Vascular endothelial growth factor (VEGF) is known as a key regulator of angiogenesis during endochondral bone formation. Recently, we demonstrated that TNF-related activation-induced cytokine (TRANCE or RANKL), which is essential for bone remodeling, also had an angiogenic activity. Here we report that VEGF up-regulates expression of receptor activator of NF-κB (RANK) and increases angiogenic responses of endothelial cells to TRANCE. Treatment of human umbilical vein endothelial cells (HUVECs) with VEGF increased both RANK mRNA and surface protein expression. Although placenta growth factor specific to VEGF receptor-1 had no significant effect on RANK expression, inhibition of downstream signaling molecules of the VEGF receptor-2 (Flk-1/KDR) such as Src, phospholipase C, protein kinase C, and phosphatidylinositol 3′-kinase suppressed VEGF-stimulated RANK expression in HUVECs. Moreover, the MEK inhibitor PD98059 or expression of dominant negative MEK1 inhibited induction of RANK by VEGF but not the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acidacetoxymethyl ester (BAPTA-AM). VEGF potentiated TRANCE-induced ERK activation and tube formation via RANK up-regulation in HUVECs. Together, these results show that VEGF enhances RANK expression in endothelial cells through Flk-1/KDR-protein kinase C-ERK signaling pathway, suggesting that VEGF plays an important role in modulating the angiogenic action of TRANCE under physiological or pathological conditions.

Original languageEnglish (US)
Pages (from-to)39548-39557
Number of pages10
JournalJournal of Biological Chemistry
Volume278
Issue number41
DOIs
StatePublished - Oct 10 2003

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Endothelial cells
Vascular Endothelial Growth Factor A
Up-Regulation
Endothelial Cells
Ligands
Human Umbilical Vein Endothelial Cells
Vascular Endothelial Growth Factor Receptor-2
Protein Kinase C
Receptor Activator of Nuclear Factor-kappa B
Bone
Chemical activation
Phosphatidylinositol 3-Kinase
Vascular Endothelial Growth Factor Receptor-1
Ethane
MAP Kinase Signaling System
Bone Remodeling
Mitogen-Activated Protein Kinase Kinases
Type C Phospholipases
Chelating Agents
Osteogenesis

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Vascular endothelial growth factor up-regulates expression of receptor activator of NF-κB (RANK) in endothelial cells. Concomitant increase of angiogenic responses to rank ligand. / Min, Jeong Ki; Kim, Young Myeong; Kim, Young Mi; Kim, Eok Cheon; Gho, Yong Song; Kang, Il Jun; Lee, Soo Young; Kong, Young Yun; Kwon, Young Guen.

In: Journal of Biological Chemistry, Vol. 278, No. 41, 10.10.2003, p. 39548-39557.

Research output: Contribution to journalArticle

Min, Jeong Ki ; Kim, Young Myeong ; Kim, Young Mi ; Kim, Eok Cheon ; Gho, Yong Song ; Kang, Il Jun ; Lee, Soo Young ; Kong, Young Yun ; Kwon, Young Guen. / Vascular endothelial growth factor up-regulates expression of receptor activator of NF-κB (RANK) in endothelial cells. Concomitant increase of angiogenic responses to rank ligand. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 41. pp. 39548-39557.
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AU - Min, Jeong Ki

AU - Kim, Young Myeong

AU - Kim, Young Mi

AU - Kim, Eok Cheon

AU - Gho, Yong Song

AU - Kang, Il Jun

AU - Lee, Soo Young

AU - Kong, Young Yun

AU - Kwon, Young Guen

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N2 - Vascular endothelial growth factor (VEGF) is known as a key regulator of angiogenesis during endochondral bone formation. Recently, we demonstrated that TNF-related activation-induced cytokine (TRANCE or RANKL), which is essential for bone remodeling, also had an angiogenic activity. Here we report that VEGF up-regulates expression of receptor activator of NF-κB (RANK) and increases angiogenic responses of endothelial cells to TRANCE. Treatment of human umbilical vein endothelial cells (HUVECs) with VEGF increased both RANK mRNA and surface protein expression. Although placenta growth factor specific to VEGF receptor-1 had no significant effect on RANK expression, inhibition of downstream signaling molecules of the VEGF receptor-2 (Flk-1/KDR) such as Src, phospholipase C, protein kinase C, and phosphatidylinositol 3′-kinase suppressed VEGF-stimulated RANK expression in HUVECs. Moreover, the MEK inhibitor PD98059 or expression of dominant negative MEK1 inhibited induction of RANK by VEGF but not the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acidacetoxymethyl ester (BAPTA-AM). VEGF potentiated TRANCE-induced ERK activation and tube formation via RANK up-regulation in HUVECs. Together, these results show that VEGF enhances RANK expression in endothelial cells through Flk-1/KDR-protein kinase C-ERK signaling pathway, suggesting that VEGF plays an important role in modulating the angiogenic action of TRANCE under physiological or pathological conditions.

AB - Vascular endothelial growth factor (VEGF) is known as a key regulator of angiogenesis during endochondral bone formation. Recently, we demonstrated that TNF-related activation-induced cytokine (TRANCE or RANKL), which is essential for bone remodeling, also had an angiogenic activity. Here we report that VEGF up-regulates expression of receptor activator of NF-κB (RANK) and increases angiogenic responses of endothelial cells to TRANCE. Treatment of human umbilical vein endothelial cells (HUVECs) with VEGF increased both RANK mRNA and surface protein expression. Although placenta growth factor specific to VEGF receptor-1 had no significant effect on RANK expression, inhibition of downstream signaling molecules of the VEGF receptor-2 (Flk-1/KDR) such as Src, phospholipase C, protein kinase C, and phosphatidylinositol 3′-kinase suppressed VEGF-stimulated RANK expression in HUVECs. Moreover, the MEK inhibitor PD98059 or expression of dominant negative MEK1 inhibited induction of RANK by VEGF but not the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acidacetoxymethyl ester (BAPTA-AM). VEGF potentiated TRANCE-induced ERK activation and tube formation via RANK up-regulation in HUVECs. Together, these results show that VEGF enhances RANK expression in endothelial cells through Flk-1/KDR-protein kinase C-ERK signaling pathway, suggesting that VEGF plays an important role in modulating the angiogenic action of TRANCE under physiological or pathological conditions.

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