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-kappa B (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 acid-acetoxymethyl 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.
Highlights
Vascular endothelial growth factor (VEGF) is known as a key regulator of angiogenesis during endochondral bone formation
VEGF potentiated TRANCE-induced extracellular signal-regulated kinase (ERK) activation and tube formation via RANK up-regulation in human umbilical vein endothelial cells (HUVECs). These results show that VEGF enhances RANK expression in endothelial cells through Flk-1/KDR-protein kinase CERK signaling pathway, suggesting that VEGF plays an important role in modulating the angiogenic action of TRANCE under physiological or pathological conditions
These results indicate that VEGF enhanced RANK mRNA and protein expression in endothelial cells
Summary
Vascular endothelial growth factor (VEGF) is known as a key regulator of angiogenesis during endochondral bone formation. We report that VEGF up-regulates expression of receptor activator of NF- B (RANK) and increases angiogenic responses of endothelial cells to TRANCE. We have demonstrated that TRANCE has a novel action of promoting angiogenesis in vivo, and the binding of TRANCE to RANK expressed on endothelial cells directly stimulates proliferation, migration, and tube formation of endothelial cells in vitro [22]. These observations suggest that the TRANCE-RANK system may be important for the processes of osteoclastogenesis and vascularization of the growth plate during bone formation and remodeling. We here show that VEGF increases RANK expression in human endothelial cells, and such endothelial RANK up-regulation results in enhancing angiogenic activities of TRANCE in endothelial cells
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