Recombinant Thrombomodulin Inhibits Thrombin-Induced Vascular Endothelial Growth Factor Production in Neuronal Cells

Sarker, Krishna Pada; Yamahata, Hitoshi; Nakata, Masao; Arisato, Takayo; Nakajima, Takeshi; Kitajima, Isao; Maruyama, Ikuro

doi:10.1159/000022522

Cited by 9 publications

(9 citation statements)

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“…The basal level of VEGF secretion has been found to be slightly but nonsignifi cantly increased compared to control followed by the administration of these pharmacological blockers. This observation is consistent with our previous fi ndings in PC12 cells [21] . We have no explanation for this phenomenon.…”

Section: Resultssupporting

confidence: 94%

“…Thrombin has also been found to induce the synthesis and secretion of nerve growth factor [22] . In addition, we and others have reported that thrombin induces VEGF production in vascular smooth muscle cells and in PC12 cells [21,23,24] . Incidentally, both thrombin and VEGF have been shown to alter the permeability of the blood-brain barrier [14][15][16] .…”

Section: Discussionmentioning

confidence: 55%

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Inhibition of Thrombin-Induced Vascular Endothelial Growth Factor Production in Human Neuroblastoma (NB-1) Cells by Argatroban

Sarker

Biswas

Yamaji

et al. 2005

Pathophysiol Haemos Thromb

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Thrombin, a serine protease that plays a pivotal role in blood coagulation, wound healing, and angiogenesis, has also been implicated in the mitogenesis of various cell types. Previously, we showed that thrombin and the thrombin receptor agonist peptide (TRAP-14; SFLLRNPNDKYEPF) for protease-activated receptor 1 (PAR1) induce vascular endothelial growth factor (VEGF) secretion in PC-12 cells. In this study, we show that thrombin and TRAP-14 also stimulate VEGF secretion in the human NB-1 neuroblastoma cells. In these cells, we further show that thrombin-induced VEGF secretion was blocked by cycloheximide and actinomycin D, indicating that de novo protein synthesis is essential for this process. Reduced thrombin-induced VEGF secretion upon treatment with LY294002, calphostin C, or BAPTA, further suggests that the process is dependent on phosphatidyl-inositol-3-kinase, protein kinase C, and calcium. However, the complete loss of thrombin-induced VEGF production upon treatment with argatroban, a derivative of arginine and a potent anticoagulant/antithrombin agent, supports the notion that argatroban serves as a useful therapeutic tool for thrombin-associated pathologic conditions. Here, it appears that argatroban may be effective in controlling disorders linked to thrombin-induced VEGF production in neuronal cells.

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Section: Resultssupporting

confidence: 94%

Section: Discussionmentioning

confidence: 55%

Inhibition of Thrombin-Induced Vascular Endothelial Growth Factor Production in Human Neuroblastoma (NB-1) Cells by Argatroban

Sarker

Biswas

Yamaji

et al. 2005

Pathophysiol Haemos Thromb

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“…The mid-to late luteal phase endometrium also experiences increased vascular permeability, accompanied by stromal edema, increased blood flow, and transudation of plasma proteins (34,55), which would enhance access of clotting factors to perivascular DC TF, and thus promote thrombin generation. Because thrombin has been reported to stimulate VEGF expression in various cell types (35)(36)(37), we theorized that it could act as a paracrine stimulator of glandular VEGF production and/or an autocrine stimulator of HESCexpressed VEGF. The current study revealed that although thrombin did not affect glandular epithelial VEGF expression, it was a potent enhancer of VEGF output in decidualized HESCs.…”

Section: Discussionmentioning

confidence: 99%

“…The luteal phase is accompanied by increased vascular permeability and stromal edema (34), which would generate thrombin via enhanced access of circulating plasma clotting factors to perivascular decidual cell (DC)-expressed TF. Because thrombin induces VEGF expression in several cell types (35)(36)(37), we hypothesized that thrombin could play a key role in regulating luteal phase endometrial VEGF expression. Thus, we evaluated thrombin effects in the presence and absence of ovarian steroids on VEGF expression in the predominant endometrial cell types, HESCs and HEGECs, and determined whether such effects are independent of hypoxia.…”

mentioning

confidence: 99%

Differential Effects of Thrombin and Hypoxia on Endometrial Stromal and Glandular Epithelial Cell Vascular Endothelial Growth Factor Expression

Lockwood¹,

Krikun²,

Koo³

et al. 2002

The Journal of Clinical Endocrinology & Metabolism

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Ovarian steroids and/or premenstrual endometrial hypoxia are thought to restore the endometrial vasculature shed during menstruation by elevating endometrial vascular endothelial growth factor (VEGF) levels. During the luteal phase, VEGF levels peak, progesterone induces estradiol (E(2))-primed human endometrial stromal cells (HESCs) to decidualize and express tissue factor (TF), and endometrial vascular permeability is enhanced. The latter would present circulating clotting factors to decidual cell-expressed TF to form local thrombin. HESCs were incubated in serum-supplemented medium containing vehicle (control) or 10(-8) M E(2) or 10(-7) M medroxyprogesterone acetate (MPA) or E(2) + MPA for 7 d to induce decidualization, while monolayers of human endometrial glandular epithelial cells (HEGECs) formed during 4-d incubation of glands. The medium was exchanged for a defined medium containing corresponding vehicle or steroids +/- thrombin under normoxia or hypoxia (0-1% O(2)). Hypoxia enhanced secreted immunoreactive VEGF levels by severalfold in HESCs and HEGECs, but the steroids did not affect VEGF output in either cell type under normoxia or hypoxia. In E(2) + MPA-decidualized HESCs, VEGF levels were elevated by 0.1 U/ml of thrombin, and 0.5-2.5 U/ml of thrombin elicited maximum effects. The addition of 0.5 U/ml of thrombin evoked a time-dependent enhancement of VEGF levels and about an 8-fold increase at 48 h (P < 0.02; n = 6). Northern blotting indicated that E(2) + MPA-decidualized HESCs expressed VEGF(121), VEGF(165), and VEGF(189) mRNA, which were enhanced severalfold during 5- to 20-h incubation with thrombin. Moreover, TRAP, a synthetic peptide activator of the constitutively expressed protease activated receptor-1 thrombin receptor in decidualized HESCs, also elevated secreted VEGF levels. By contrast, HEGECs were unresponsive to thrombin added alone or with ovarian steroids. These results suggest that thrombin formed by progestin-augmented TF levels acts as an autocrine enhancer of VEGF expression in decidualized HESCs. Because angiogenesis occurs in a matrix of decidualized HESCs, these in vitro results provide a novel mechanism to account for both the peak in VEGF and angiogenesis in luteal phase human endometrium.

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“…PARs regulate some of the pathological effects of thrombin and are involved in CNS pathophysiology in some animal studies (121). Thrombin is associated with permeability change in the BBB leading to edema through chemotaxin and MMP activation, as well as the release of vascular endothelial growth factor (VEGF) from neurons through receptor activation (122). VEGF increased vascular permeability and vasodilation via nitric oxide induction and may serve as a potential fuel for free radical generation (59).…”

Section: Phe After Ichmentioning

confidence: 99%

Secondary Hematoma Expansion and Perihemorrhagic Edema after Intracerebral Hemorrhage: From Bench Work to Practical Aspects

Lim-Hing

Rincón

2017

Front. Neurol.

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Intracerebral hemorrhages (ICH) represent about 10–15% of all strokes per year in the United States alone. Key variables influencing the long-term outcome after ICH are hematoma size and growth. Although death may occur at the time of the hemorrhage, delayed neurologic deterioration frequently occurs with hematoma growth and neuronal injury of the surrounding tissue. Perihematoma edema has also been implicated as a contributing factor for delayed neurologic deterioration after ICH. Cerebral edema results from both blood–brain barrier disruption and local generation of osmotically active substances. Inflammatory cellular mediators, activation of the complement, by-products of coagulation and hemolysis such as thrombin and fibrin, and hemoglobin enter the brain and induce a local and systemic inflammatory reaction. These complex cascades lead to apoptosis or neuronal injury. By identifying the major modulators of cerebral edema after ICH, a therapeutic target to counter degenerative events may be forthcoming.

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Recombinant Thrombomodulin Inhibits Thrombin-Induced Vascular Endothelial Growth Factor Production in Neuronal Cells

Cited by 9 publications

References 50 publications

Inhibition of Thrombin-Induced Vascular Endothelial Growth Factor Production in Human Neuroblastoma (NB-1) Cells by Argatroban

Inhibition of Thrombin-Induced Vascular Endothelial Growth Factor Production in Human Neuroblastoma (NB-1) Cells by Argatroban

Differential Effects of Thrombin and Hypoxia on Endometrial Stromal and Glandular Epithelial Cell Vascular Endothelial Growth Factor Expression

Secondary Hematoma Expansion and Perihemorrhagic Edema after Intracerebral Hemorrhage: From Bench Work to Practical Aspects

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