Vascular endothelial growth factor induces protein kinase D-dependent production of proinflammatory cytokines in endothelial cells

2009 ◽  
Vol 296 (4) ◽  
pp. C821-C827 ◽  
Author(s):  
Qin Hao ◽  
Linping Wang ◽  
Hua Tang
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Protein Kinase ◽  
Proinflammatory Cytokines ◽  
Proinflammatory Cytokine ◽  
Cytokine Production ◽  
Protein Kinase D ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Emerging evidence indicates that vascular endothelial growth factor (VEGF) plays a critical role in host inflammatory responses in several disease states, including atherosclerosis, sepsis, and rheumatoid arthritis. In this study, we determined the effect of VEGF on endothelial induction of proinflammatory cytokines and investigated the responsible signal pathways. By using a cytokine antibody array that detects the end point protein products released from endothelial cells (ECs), we found that VEGF, via VEGF receptor 2 (VEGFR2), predominantly induced the production of proinflammatory cytokine interleukin (IL)-6 and CXC chemokines IL-8 and growth-related oncogene-α (GRO-α) in ECs but not in leukocytes among 36 cytokines in the array. The production of these inflammatory cytokines by VEGF was much stronger than the induction of cell adhesion molecule in ECs. We further found that the cytokine production by VEGF was essentially mediated by the Gö-6976-sensitive protein kinase D (PKD) family kinases. Importantly, the VEGF-induced production of IL-6, IL-8, and GRO-α was inhibited ∼70%, 40%, or 37% by PKD1 silencing (more than 90% knockdown) with three small interference RNAs that target different PKD1 regions. Moreover, silencing PKD2 downregulated VEGFR2 and markedly inhibited the cytokine production by VEGF in ECs. Our results indicate that VEGF, via VEGFR2-PKD1 axis, induces the production of proinflammatory cytokine IL-6, IL-8, and GRO-α in ECs but not in leukocytes, which may offer new insights into the mechanism of the proinflammatory activity of VEGF.

Vascular endothelial growth factor (VEGF)–C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy

Blood ◽  
2002 ◽  
Vol 99 (6) ◽  
pp. 2179-2184 ◽  
Author(s):  
Sergio Dias ◽  
Margaret Choy ◽  
Kari Alitalo ◽  
Shahin Rafii
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Proinflammatory Cytokines ◽  
Chemotherapeutic Agents ◽  
Leukemic Cells ◽  
Binding Motif ◽  
Mutant Form ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Abstract Similar to solid tumors, growth of leukemias may also be angiogenesis dependent. Furthermore, tyrosine kinase receptors specific to endothelial cells are expressed on certain subsets of leukemias. We have previously demonstrated the existence of a VEGF/VEGFR-2 autocrine loop on leukemic cells that supports their growth and migration. Here, we demonstrate that in response to leukemia-derived proangiogenic and proinflammatory cytokines such as basic fibroblast growth factor and IL-1, endothelial cells release increasing amounts of another vascular endothelial growth factor (VEGF) family member, VEGF-C. In turn, interaction of VEGF-C with its receptor VEGFR-3 (FLT-4) promotes leukemia survival and proliferation. We demonstrate in 2 cell lines and 5 FLT-4+ leukemias that VEGF-C and a mutant form of the molecule that lacks the KDR-binding motif induce receptor phosphorylation, leukemia proliferation, and increased survival, as determined by increased Bcl-2/Bax ratios. Moreover, VEGF-C protected leukemic cells from the apoptotic effects of 3 chemotherapeutic agents. Because most leukemic cells release proangiogenic as well as proinflammatory cytokines, our data suggest that the generation of a novel paracrine angiogenic loop involving VEGF-C and FLT-4 may promote the survival of a subset of leukemias and protect them from chemotherapy-induced apoptosis. These results identify the VEGF-C/FLT-4 pathway as a novel therapeutic target for the treatment of subsets of acute leukemia.

Vascular Endothelial Growth Factor Enhances the Expression of Urokinase Receptor in Human Endothelial Cells via Protein Kinase C Activation

2001 ◽  
Vol 85 (02) ◽  
pp. 296-302 ◽  
Author(s):  
Marielle Kroon ◽  
Pieter Koolwijk ◽  
Mario Vermeer ◽  
Bea van der Vecht ◽  
Victor van Hinsbergh
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Protein Kinase C ◽  
Growth Factor ◽  
Protein Kinase ◽  
Receptor Expression ◽  
Vascular Endothelial ◽  
Human Endothelial Cells ◽  
Kinase C ◽  
Endothelial Growth Factor

SummaryAmong other proteolytic enzymes, the urokinase-type plasminogen activator (u-PA)/plasmin cascade contributes to cell migration and the formation of capillary-like structures in a fibrinous exudate. The u-PA receptor (u-PAR) focuses proteolytical activity on the cell surface of the endothelial cell and hereby accelerates the pericellular matrix degradation. Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)-2 enhance u-PA receptor expression in human endothelial cells. In this paper we show that the protein kinase C (PKC) inhibitors Ro31-8220 and GF109203X inhibit VEGF165-induced u-PAR antigen expression in human endothelial cells, whereas PKC inhibition had no effect on FGF-2-induced u-PAR antigen enhancement. In addition, inhibition of PKC activity had no effect on VEGF165-or FGF-2-induced proliferation in human endothelial cells. We conclude that VEGF165 induces u-PAR via a PKC-dependent pathway, whereas proliferation is induced via a different pathway probably involving tyrosine phosphorylation of proteins downstream of the VEGF receptors.

Glomerular endothelial cells in culture express and secrete vascular endothelial growth factor

1994 ◽  
Vol 266 (1) ◽  
pp. F81-F88 ◽  
Author(s):  
K. Uchida ◽  
S. Uchida ◽  
K. Nitta ◽  
W. Yumura ◽  
F. Marumo ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Protein Kinase ◽  
Mrna Abundance ◽  
Vascular Endothelial ◽  
Vegf Expression ◽  
Vegf Mrna ◽  
Glomerular Endothelial Cells ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is a specific growth factor for endothelial cells, and its abundant expression has been reported in kidney glomeruli. In this study, we focused on glomerular endothelial cells (GEN) as a possible source of VEGF secretion and sought to uncover a potential autocrine role of VEGF for GEN. Ribonuclease protection assay demonstrated VEGF mRNA expression in cultured GEN, and 46-kDa VEGF protein was detected in the conditioned medium by immunoblot analysis using polyclonal antibody raised against the NH2-terminal portion of VEGF. Removal of fetal bovine serum (FBS) from the culture medium for 2 h decreased VEGF mRNA abundance, which was restored by the readdition of FBS (10%) within 2 h. The effect of FBS was completely abolished by protein kinase inhibitor H-7 (10 microM), suggesting that FBS-stimulated VEGF mRNA induction involves activation of protein kinases. The treatment of GEN with 10(-7) M 12-O-tetradecanoylphorbol-13-acetate (TPA) increased the VEGF mRNA abundance fivefold, supporting the idea that VEGF expression is regulated by protein kinase C. [3H]thymidine incorporation into GEN treated with TPA (10(-7) M) was inhibited by neutralizing antibody for VEGF. Thus VEGF was identified as an autocrine growth factor for GEN in vitro. Its physiological role might be the regulation of GEN proliferation, and the induction of VEGF expression by FBS and TPA suggests its involvement in the response of glomerular capillary endothelial cells to injury in certain pathophysiological states.

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