Suppression of c-Cbl Tyrosine Phosphorylation Inhibits Neointimal Formation in Balloon-Injured Rat Arteries

Tang, Zhihui; Wang, Ying; Fan, Yanbo; Zhu, Yi; Chien, Shu; Wang, Nanping

doi:10.1161/circulationaha.107.761932

Cited by 26 publications

(22 citation statements)

References 44 publications

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“…Equal amounts of protein were run on 10 % SDS-PAGE and blotted onto polyvinylidene difluoride membranes. The blots were reacted with primary antibodies against HIF-1a (BD Pharmingen), PTEN (Epitomics), eNOS (BD Pharmingen), phosphorylated (p)-eNOS (S1177), p-Akt (S473) and Akt (Cell Signaling Technology), respectively, followed by the reaction with the appropriate secondary antibodies and the detection with the enhanced chemiluminescence kit as described previously [15].…”

Section: Western Blottingmentioning

confidence: 99%

Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer

et al. 2015

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Angiogenesis, a crucial step in tumor growth and metastasis, is regulated by various pro- or anti-angiogenic factors. Recently, microRNAs have been shown to modulate angiogenic processes by modulating the expression of critical angiogenic factors. However, roles of tumor-derived microRNAs in regulating tumor vascularization remain to be elucidated. In this study, we found that delivery of miR-494 into human vascular endothelial cells (ECs) enhanced the EC migration and promoted angiogenesis. The angiogenic effect of miR-494 was mediated by the targeting of PTEN and the subsequent activation of Akt/eNOS pathway. Importantly, co-culture experiments demonstrated that a lung cancer cell line, A549, secreted and delivered miR-494 into ECs via a microvesicle-mediated route. In addition, we found that the expression of miR-494 was induced in the tumor cells in response to hypoxia, likely via a HIF-1α-mediated mechanism. Furthermore, a specific miR-494 antagomiR effectively inhibited angiogenesis and attenuated the growth of tumor xenografts in nude mice. Taken together, these results demonstrated that miR-494 is a novel tumor-derived paracrine signal to promote angiogenesis and tumor growth under hypoxic condition.

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Section: Western Blottingmentioning

confidence: 99%

Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer

et al. 2015

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“…7 For cell cycle analysis, VSMCs synchronized by serum starvation for 48 hours were treated with PDGF-BB (Sigma-Aldrich) …”

Section: Cell Proliferation and Cell Cyclementioning

confidence: 99%

“…7 For cell cycle analysis, VSMCs synchronized by serum starvation for 48 hours were treated with PDGF-BB (Sigma-Aldrich) for 16 hours. Cells were harvested, fixed, and stained with use of Cycle Test Plus DNA Reagent Kit (Becton Dickinson) and analyzed for DNA content by flow cytometry by FACScan (Becton Dickinson).…”

Section: Cell Proliferation and Cell Cyclementioning

confidence: 99%

Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Zhu

Xue

Zhao

et al. 2011

ATVB

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Objective-Restenosis after angioplasty remains a major clinical problem. Prostaglandin E 2 (PGE 2 ) plays an important role in vascular homeostasis. The PGE 2 receptor E-prostanoid 2 (EP2) is involved in the proliferation and migration of various cell types. We aimed to determine the role of EP2 in the pathogenesis of neointimal formation after vascular injury. Methods and Results-Wire-mediated vascular injury was induced in the femoral arteries of male wild-type (EP2ϩ/ϩ) and EP2 gene-deficient (EP2Ϫ/Ϫ) mice. In EP2ϩ/ϩ mice, EP2 mRNA expression was increased in injured vessels for at least 4 weeks after vascular injury. Neointimal hyperplasia was markedly accelerated in EP2Ϫ/Ϫ mice, which was associated with increased proliferation and migration of vascular smooth muscle cells (VSMCs) and increased cyclin D1 expression in the neointima layer. Platelet-derived growth factor-BB (PDGF-BB) treatment resulted in more significant cell proliferation and migration in VSMCs of EP2Ϫ/Ϫ mice than in those of EP2ϩ/ϩ mice. Activation and overexpression of EP2 attenuated PDGF-BB-elicited cell proliferation and migration, induced G 1 3 S-phase arrest and reduced PDGF-BB-stimulated extracellular signal-regulated kinase phosphorylation in EP2ϩ/ϩ VSMCs. Conclusion-These findings reveal a novel role of the EP2 receptor in neointimal hyperplasia after arterial injury. The EP2 receptor may represent a potential therapeutic target for restenosis after angioplasty. (Arterioscler Thromb Vasc Biol. 2011;31:1739-1747.)Key Words: angioplasty Ⅲ eicosanoids Ⅲ prostaglandins Ⅲ receptors Ⅲ restenosis P ercutaneous transluminal coronary angioplasty (PTCA) has been widely used for treating coronary atherosclerosis. However, many patients undergoing PTCA experience postangioplasty restenosis. 1 Although new devices for dilatation of stenosed arteries have lowered the incidence of acute complications, restenosis remains a major obstacle in the long-term outcome of PTCA interventions. 2 Restenosis is defined as the healing response of the arterial wall to mechanical injury and consists of 2 main processes: neointimal hyperplasia (smooth muscle migration/proliferation and extracellular matrix deposition) and vessel remodeling. 3 Platelet-derived growth factor-BB (PDGF-BB), an important growth factor released from platelets and leukocytes, plays a critical role in intimal hyperplasia after vascular injury. 4,5 An enormous amount of research has elucidated the molecular pathways involved in neointimal formation and vascular remodeling after vascular injury and has greatly advanced our understanding of the mechanisms contributing to the pathogenesis of restenosis. 6 -8 These efforts have led to many new strategies for effective prevention and treatment options for restenosis.Prostaglandin E 2 (PGE 2 ), a major arachidonic acid metabolite, is produced in the vasculature via a mechanism dependent on cyclooxygenase (COX) and prostaglandin E synthase. PGE 2 has important roles in the regulation of blood pressure, inflammatory response, immune response, an...

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“…These results include the following: (1) β‐arrestin2, but not β‐arrestin1, knockout mice had a reduced neointimal hyperplasia in wire‐injured carotid arteries70; and (2) the roles of the mTOR pathway in neointima hyperplasia have been well established with the successful use of sirolimus (rapamycin)–eluting stents in angioplasty. We previously also showed that the activation of mTOR in the neointima in balloon‐injured rat carotid arteries and perivascular delivery of rapamycin in pluronic gel decreased neointima formation 37, 38. In addition, sirolimus ameliorated hypercontractility to 5‐HT in balloon‐injured porcine coronary arteries 4…”

Section: Discussionmentioning

confidence: 90%

“…Activation of mTOR pathway mediated SMC migration and was implicated in vascular neointimal hyperplasia 37, 38, 39. Thus, we examined the effect of 5‐HT2BR on the activation of mTOR and its downstream serine/threonine kinase p70S6K.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of 5‐Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β‐Arrestin2–Mammalian Target of Rapamycin/p70S6K Pathway

Liu

Wang

et al. 2018

JAHA

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BackgroundAs a monoamine neurotransmitter, 5‐hydroxytryptamine (5‐HT) or serotonin modulates mood, appetite, and sleep. Besides, 5‐HT also has important peripheral functions. 5‐HT receptor 2B (5‐HT2BR) plays a key role in cardiovascular diseases, such as pulmonary arterial hypertension and cardiac valve disease. Percutaneous intervention has been used to restore blood flow in occlusive vascular disease. However, restenosis remains a significant problem. Herein, we investigated the role of 5‐HT2BR in neointimal hyperplasia, a key pathological process in restenosis.Methods and ResultsThe expression of 5‐HT2BR was upregulated in wire‐injured mouse femoral arteries. In addition, BW723C86, a selective 5‐HT2BR agonist, promoted the injury response during restenosis. 5‐HT and BW723C86 stimulated migration and proliferation of rat aortic smooth muscle cells. Conversely, LY272015, a selective antagonist, attenuated the 5‐HT–induced smooth muscle cell migration and proliferation. In vitro study showed that the promigratory effects of 5‐HT2BR were mediated through the activation of mammalian target of rapamycin (mTOR)/p70S6K signaling in a β‐arrestin2–dependent manner. Inhibition of mammalian target of rapamycin or p70S6K mitigated 5‐HT2BR–mediated smooth muscle cell migration. Mice with deficiency of 5‐HT2BR showed significantly reduced neointimal formation in wire‐injured arteries.ConclusionsThese results demonstrated that activation of 5‐HT2BR and β‐arrestin2–biased downstream signaling are key pathological processes in neointimal formation, and 5‐HT2BR may be a potential target for the therapeutic intervention of vascular restenosis.

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Suppression of c-Cbl Tyrosine Phosphorylation Inhibits Neointimal Formation in Balloon-Injured Rat Arteries

Cited by 26 publications

References 44 publications

Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer

Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer

Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Inhibition of 5‐Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β‐Arrestin2–Mammalian Target of Rapamycin/p70S6K Pathway

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Suppression of c-Cbl Tyrosine Phosphorylation Inhibits Neointimal Formation in Balloon-Injured Rat Arteries

Cited by 26 publications

References 44 publications

Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer

Tumor-derived microRNA-494 promotes angiogenesis in non-small cell lung cancer

Targeted Disruption of the Prostaglandin E 2 E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice

Inhibition of 5‐Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β‐Arrestin2–Mammalian Target of Rapamycin/p70S6K Pathway

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Targeted Disruption of the Prostaglandin E ₂ E-Prostanoid 2 Receptor Exacerbates Vascular Neointimal Formation in Mice