scholarly journals Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways

Blood ◽  
2005 ◽  
Vol 106 (10) ◽  
pp. 3423-3431 ◽  
Author(s):  
Ahmad Salameh ◽  
Federico Galvagni ◽  
Monia Bardelli ◽  
Federico Bussolino ◽  
Salvatore Oliviero
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Capillary Plexus ◽  
Primary Capillary Plexus ◽  
Umbilical Vein Endothelial Cells

AbstractVascular endothelial growth factor receptor-3 (VEGFR-3) plays a key role for the remodeling of the primary capillary plexus in the embryo and contributes to angiogenesis and lymphangiogenesis in the adult. However, VEGFR-3 signal transduction pathways remain to be elucidated. Here we investigated VEGFR-3 signaling in primary human umbilical vein endothelial cells (HUVECs) by the systematic mutation of the tyrosine residues potentially involved in VEGFR-3 signaling and identified the tyrosines critical for its function. Y1068 was shown to be essential for the kinase activity of the receptor. Y1063 signals the receptor-mediated survival by recruiting CRKI/II to the activated receptor, inducing a signaling cascade that, via mitogen-activated protein kinase kinase-4 (MKK4), activates c-Jun N-terminal kinase-1/2 (JNK1/2). Inhibition of JNK1/2 function either by specific peptide inhibitor JNKI1 or by RNA interference (RNAi) demonstrated that activation of JNK1/2 is required for a VEGFR-3–dependent prosurvival signaling. Y1230/Y1231 contributes, together with Y1337, to proliferation, migration, and survival of endothelial cells. Phospho-Y1230/Y1231 directly recruits growth factor receptor–bonus protein (GRB2) to the receptor, inducing the activation of both AKT and extracellular signal–related kinase 1/2 (ERK1/2) signaling. Finally, we observed that Y1063 and Y1230/Y1231 signaling converge to induce c-JUN expression, and RNAi experiments demonstrated that c-JUN is required for growth factor–induced prosurvival signaling in primary endothelial cells.

scholarly journals FGF-1-dependent proliferative and migratory responses are impaired in senescent human umbilical vein endothelial cells and correlate with the inability to signal tyrosine phosphorylation of fibroblast growth factor receptor-1 substrates.

1996 ◽  
Vol 134 (3) ◽  
pp. 783-791 ◽  
Author(s):  
S Garfinkel ◽  
X Hu ◽  
I A Prudovsky ◽  
G A McMahon ◽  
E M Kapnik ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Tyrosine Phosphorylation ◽  
Umbilical Vein ◽  
Growth Factor Receptor ◽  
Signal Transduction Pathway ◽  
Cell Populations ◽  
Src Tyrosine Kinase ◽  
Human Umbilical Vein ◽  
Umbilical Vein Endothelial Cells

Senescent cells do not proliferate in response to exogenous growth factors, yet the number and affinity of growth factor receptors on the cell surface appear to be similar to presenescent cell populations. To determine whether a defect in receptor signaling exists, we analyzed human umbilical vein endothelial cells (HUVEC) since HUVEC growth is absolutely dependent upon the presence of FGF. We report that in both presenescent and senescent HUVEC populations, FGF-1 induces the expression of cell cycle-specific genes, suggesting that functional FGF receptor (FGFR) may exist on the surface of these cells. However, the tyrosine phosphorylation of FGFR-1 substrates, Src and cortactin, is impaired in senescent HUVEC, and only the presenescent cell populations exhibit a FGF-1-dependent Src tyrosine kinase activity. Moreover, we demonstrate that senescent HUVEC are unable to migrate in response to FGF-1, and these data correlate with an altered organization of focal adhesion sites. These data suggest that the induction of gene expression is insufficient to promote a proliferative or migratory phenotype in senescent HUVEC and that the attenuation of the FGFR-1 signal transduction pathway may be involved in the inability of senescent HUVEC to proliferate and/or migrate.

scholarly journals p38 Mitogen-Activated Protein Kinase Mediates Lipopolysaccharide and Tumor Necrosis Factor Alpha Induction of Shiga Toxin 2 Sensitivity in Human Umbilical Vein Endothelial Cells

2007 ◽  
Vol 76 (3) ◽  
pp. 1115-1121 ◽  
Author(s):  
Matthew K. Stone ◽  
Glynis L. Kolling ◽  
Matthew H. Lindner ◽  
Tom G. Obrig
Keyword(s):  
Endothelial Cells ◽  
Intracellular Signaling ◽  
Umbilical Vein ◽  
Mitogen Activated Protein Kinase ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Mitogen Activated Protein ◽  
Shiga Toxin 2 ◽  
Factor Alpha ◽  
Umbilical Vein Endothelial Cells

ABSTRACTEscherichia coliO157:H7 Shiga toxin 2 (Stx2), one of the causative agents of hemolytic-uremic syndrome, is toxic to endothelial cells, including primary cultured human umbilical vein endothelial cells (HUVEC). This sensitivity of cells to Stx2 can be increased with either lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-α). The goal of the present study was to identify the intracellular signaling pathway(s) by which LPS and TNF-α sensitize HUVEC to the cytotoxic effects of Stx2. To identify these pathways, specific pharmacological inhibitors and small interfering RNAs were tested with cell viability endpoints. A time course and dose response experiment for HUVEC exposure to LPS and TNF-α showed that a relatively short exposure to either agonist was sufficient to sensitize the cells to Stx2 and that both agonists stimulated intracellular signaling pathways within a short time. Cell viability assays indicated that the p38 mitogen-activated protein kinase (MAPK) inhibitors SB202190 and SB203580 and the general protein synthesis inhibitor cycloheximide inhibited both the LPS and TNF-α sensitization of HUVEC to Stx2, while all other inhibitors tested did not inhibit this sensitization. Additionally, SB202190 reduced the cellular globotriaosylceramide content under LPS- and TNF-α-induced conditions. In conclusion, our results show that LPS and TNF-α induction of Stx2 sensitivity in HUVEC is mediated through a pathway that includes p38 MAPK. These results indicate that inhibition of p38 MAPK in endothelial cells may protect a host from the deleterious effects of Stx2.

scholarly journals MiRNA-575 suppresses angiogenesis by targeting Rab5-MEK-ERK pathway in endothelial cells

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Xin Zhao ◽  
Yaping Yi ◽  
Chao Meng ◽  
Ningyuan Fang
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Intima Media Thickness ◽  
Carotid Intima Media Thickness ◽  
Mitogen Activated Protein Kinase ◽  
Hypertensive Patients ◽  
Downstream Target ◽  
Potential Biomarker ◽  
Mitogen Activated Protein ◽  
Umbilical Vein Endothelial Cells

AbstractHypertension is a major risk factor for the development of atherosclerosis. Increased carotid intima-media thickness (CIMT) is generally considered as an early marker of atherosclerosis. Recently, circulating miRNAs have been implicated both as sensitive biomarkers and key regulators in the development of atherosclerosis. However, the biological functions and molecular regulatory mechanisms for miR-575 on angiogenesis remain unknown. In our study, we first identified up-regulation of circulating miR-575 in plasma of essential hypertensive patients with increased CIMT (iCIMT) compared with those patients with normal CIMT (nCIMT). Furthermore, the overexpression of miR-575 in human umbilical vein endothelial cells (HUVECs) by its mimics significantly inhibited migration and proliferation as well as induction of apoptosis of HUVECs. Inhibition of miR-575 performed the reverse effects of HUVECs. We further suggested Rab5B was the downstream target of miR-575 and knockdown of Rab5B significantly inhibited migration and proliferation of HUVECs. Overexpression of Rab5B largely rescued the miR-575-mediated impairment of angiogenesis processes including: cell proliferation, migration, and apoptosis as well as activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK) signaling. Therefore, our results uncover a novel role of miR-575 in endothelial cells, implying a potential biomarker and clinical target for atherosclerosis in hypertensive patients.

Agonist-specific cross talk between ERKs and p38mapk regulates PGI2 synthesis in endothelium

2001 ◽  
Vol 281 (4) ◽  
pp. C1266-C1276 ◽  
Author(s):  
Rebecca A. Houliston ◽  
Jeremy D. Pearson ◽  
Caroline P. D. Wheeler-Jones
Keyword(s):  
Cross Talk ◽  
Umbilical Vein ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Assay ◽  
Erk Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Interleukin 1Α ◽  
Umbilical Vein Endothelial Cells ◽  
Sb 203580

We have examined the mechanisms regulating prostacyclin (PGI2) synthesis after acute exposure of human umbilical vein endothelial cells (HUVEC) to interleukin-1α (IL-1α). IL-1α evoked an early (30 min) release of PGI2 and [3H]arachidonate that was blocked by the cytosolic phospholipase A2α (cPLA2α) inhibitor arachidonyl trifluoromethyl ketone. IL-1α-mediated activation of extracellular signal-regulated kinase 1/2 (ERK1/2; p42/p44mapk) coincided temporally with phosphorylation of cPLA2α and with the onset of PGI2synthesis. The mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors, PD-98059 and U-0126, blocked IL-1α-induced ERK activation and partially attenuated cPLA2α phosphorylation and PGI2 release, suggesting that ERK-dependent and -independent pathways regulate cPLA2α phosphorylation. SB-203580 treatment enhanced IL-1α-induced MEK, p42/44mapk, and cPLA2α phosphorylation but reduced thrombin-stimulated MEK and p42/44mapk activation. IL-1α, but not thrombin, activated Raf-1 as assessed by immune-complex kinase assay, as did SB-203580 alone. These results show that IL-1α causes an acute upregulation of PGI2generation in HUVEC, establish a role for the MEK/ERK/cPLA2α pathway in this early release, and provide evidence for an agonist-specific cross talk between p38mapkand p42/44mapk that may reflect receptor-specific differences in the signaling elements proximal to MAPK activation.

Anandamide induces apoptosis in human endothelial cells: its regulation system and clinical implications

2003 ◽  
Vol 89 (05) ◽  
pp. 875-884 ◽  
Author(s):  
Kazuyo Yamaji ◽  
Krishna Sarker ◽  
Koichi Kawahara ◽  
Satoshi Iino ◽  
Munekazu Yamakuchi ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Crucial Role ◽  
Umbilical Vein ◽  
Mitogen Activated Protein Kinase ◽  
Regulation System ◽  
Dependent Manner ◽  
Vanilloid Receptor 1 ◽  
Mitogen Activated Protein ◽  
Umbilical Vein Endothelial Cells ◽  
Endogenous Cannabinoid

SummaryAnandamide (AEA), an endogenous cannabinoid, is generated by macrophages during shock conditions, and is thought to be a causative mediator of septic shock. Thus, we hypothesized that AEA plays a crucial role in endothelial cell (EC) injury. Here, we demonstrate that AEA induces apoptosis in a time-and dose-dependent manner in human umbilical vein endothelial cells (HUVECs). AEA triggered phosphorylation of c-Jun NH2-terminal kinase (JNK) and p38 mitogen activated protein kinase. AEA also showed a marked increase of interleukin 1β–converting enzyme (ICE)CED-3 family protease (caspase-3) activity. AEA-induced EC death was inhibited by a selective vanilloid receptor 1 (VR1) antagonist, capsazepine, and was enhanced by a VR1 agonist, capsaicin, indicating that AEA induces apoptosis in ECs via VR1. In conclusion, we propose that AEA may play a crucial role in EC injury under conditions of shock, and that the use of inhibitors of the AEA regulation system may have a therapeutic effect under these conditions.

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