Thrombin, TNF-α, and LPS exert overlapping but nonidentical effects on gene expression in endothelial cells and vascular smooth muscle cells

Wu, Sheng-Qian; Aird, William C.

doi:10.1152/ajpheart.00993.2004

Cited by 42 publications

(40 citation statements)

References 62 publications

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“…21,25 To more comprehensively define these patterns, we used DNA microarrays to assay transcriptional profiles in HUVECs treated in the absence or presence of VEGF, thrombin, or TNF-␣ for 1, 4, and 18 hours. As shown in Figure 1A, the majority of thrombin-responsive genes were up-regulated at 4 hours, whereas VEGF-and TNF-␣-responsive genes were most highly represented at 18 hours.…”

Section: Resultsmentioning

confidence: 99%

Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3

Suehiro

Hamakubo

Kodama

et al. 2010

Blood

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Endothelial cell activation and dysfunction underlie many vascular disorders, including atherosclerosis, tumor growth, and sepsis. Endothelial cell activation, in turn, is mediated primarily at the level of gene transcription. Here, we show that in response to several activation agonists, including vascular endothelial growth factor (VEGF), tumor necrosis factor-α, and thrombin, endothelial cells demonstrate rapid and profound induction of the early growth response (Egr) genes egr-1 and egr-3. In VEGF-treated endothelial cells, induction of Egr-3 was far greater and more prolonged compared with Egr-1. VEGF-mediated stimulation of Egr-3 involved the inducible binding of NFATc, serum response factor, and CREB to their respective consensus motifs in the upstream promoter region of Egr-3. Knockdown of Egr-3 markedly impaired VEGF-mediated proliferation, migration, and tube formation of endothelial cells and blocked VEGF-induced monocyte adhesion. Egr-3 knockdown abrogated VEGF-mediated vascular outgrowth from ex vivo aortic rings and attenuated Matrigel plug vascularization and melanoma tumor growth in vivo. Together, these findings suggest that Egr-3 is a critical determinant of VEGF signaling in activated endothelial cells. Thus, Egr-3 represents a potential therapeutic target in VEGF-mediated vasculopathic diseases.

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Section: Resultsmentioning

confidence: 99%

Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3

Suehiro

Hamakubo

Kodama

et al. 2010

Blood

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“…Upon bacterial insult, both autocrine-and paracrine-derived ROS affect the endothelium, leading to altered gene expression and protein modification, resulting in organ failure (43). We have shown previously that paracrine-derived ROS activates EC Ca 2+ mobilization (15).…”

Section: Discussionmentioning

confidence: 99%

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Gandhirajan¹,

Meng²,

et al. 2013

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During sepsis, acute lung injury (ALI) results from activation of innate immune cells and endothelial cells by endotoxins, leading to systemic inflammation through proinflammatory cytokine overproduction, oxidative stress, and intracellular Ca 2+ overload. Despite considerable investigation, the underlying molecular mechanism(s) leading to LPS-induced ALI remain elusive. To determine whether stromal interaction molecule 1-dependent (STIM1-dependent) signaling drives endothelial dysfunction in response to LPS, we investigated oxidative and STIM1 signaling of EC-specific Stim1-knockout mice. Here we report that LPSmediated Ca 2+ oscillations are ablated in ECs deficient in Nox2, Stim1, and type II inositol triphosphate receptor (Itpr2). LPS-induced nuclear factor of activated T cells (NFAT) nuclear accumulation was abrogated by either antioxidant supplementation or Ca 2+ chelation. Moreover, ECs lacking either Nox2 or Stim1 failed to trigger store-operated Ca 2+ entry (SOCe) and NFAT nuclear accumulation. LPS-induced vascular permeability changes were reduced in EC-specific Stim1 -/-mice, despite elevation of systemic cytokine levels. Additionally, inhibition of STIM1 signaling prevented receptor-interacting protein 3-dependent (RIP3-dependent) EC death. Remarkably, BTP2, a small-molecule calcium release-activated calcium (CRAC) channel blocker administered after insult, halted LPS-induced vascular leakage and pulmonary edema. These results indicate that ROS-driven Ca 2+ signaling promotes vascular barrier dysfunction and that the SOCe machinery may provide crucial therapeutic targets to limit sepsis-induced ALI.

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“…7 and bacterial toxins such as lipopolysaccharide (LPS). 8 All these circulating molecules and agents can recognize countermolecules (receptors) expressed on the ECs and trigger an increase in vessel permeability favoring the paracellular transport.…”

Section: Introductionmentioning

confidence: 99%

Probing the mechanical properties of TNF-α stimulated endothelial cell with atomic force microscopy

Lee¹,

Zaske²,

Novellino³

et al. 2011

IJN

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TNF-α (tumor necrosis factor-α) is a potent pro-inflammatory cytokine that regulates the permeability of blood and lymphatic vessels. The plasma concentration of TNF-α is elevated (> 1 pg/mL) in several pathologies, including rheumatoid arthritis, atherosclerosis, cancer, pre-eclampsia; in obese individuals; and in trauma patients. To test whether circulating TNF-α could induce similar alterations in different districts along the vascular system, three endothelial cell lines, namely HUVEC, HPMEC, and HCAEC, were characterized in terms of 1) mechanical properties, employing atomic force microscopy; 2) cytoskeletal organization, through fluorescence microscopy; and 3) membrane overexpression of adhesion molecules, employing ELISA and immunostaining. Upon stimulation with TNF-α (10 ng/mL for 20 h), for all three endothelial cells, the mechanical stiffness increased by about 50% with a mean apparent elastic modulus of E ~5 ± 0.5 kPa (~3.3 ± 0.35 kPa for the control cells); the density of F-actin filaments increased in the apical and median planes; and the ICAM-1 receptors were overexpressed compared with controls. Collectively, these results demonstrate that sufficiently high levels of circulating TNF-α have similar effects on different endothelial districts, and provide additional information for unraveling the possible correlations between circulating pro-inflammatory cytokines and systemic vascular dysfunction.

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Thrombin, TNF-α, and LPS exert overlapping but nonidentical effects on gene expression in endothelial cells and vascular smooth muscle cells

Abstract: Wu, Sheng-Qian, and William C. Aird. Thrombin, TNF-␣, and LPS exert overlapping but nonidentical effects on gene expression in endothelial cells and vascular smooth muscle cells.

Cited by 42 publications

References 62 publications

Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3

Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Probing the mechanical properties of TNF-α stimulated endothelial cell with atomic force microscopy

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Thrombin, TNF-α, and LPS exert overlapping but nonidentical effects on gene expression in endothelial cells and vascular smooth muscle cells

Abstract: Wu, Sheng-Qian, and William C. Aird. Thrombin, TNF-␣, and LPS exert overlapping but nonidentical effects on gene expression in endothelial cells and vascular smooth muscle cells.

Cited by 42 publications

References 62 publications

Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3

Vascular endothelial growth factor activation of endothelial cells is mediated by early growth response-3

Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation

Probing the mechanical properties of TNF-&alpha; stimulated endothelial cell with atomic force microscopy

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Probing the mechanical properties of TNF-α stimulated endothelial cell with atomic force microscopy