Expression of endothelin 1 and its angiogenic role in meningiomas
ABSTRACT Meningiomas are one of the most frequent central nervous system tumours. Although slow-growing at times, they continue to be a cause of morbidity and mortality. The endothelin (ET) family consists of three isoforms: ET-1 is the most abundant one. ET-1 may be involved in meningioma tumourigenesis in concert with other growth factors, in particular with angiogenic agents. We analysed ET-1 expression by immunohistochemistry and its activating system by reverse-transcription-polymerase chain reaction in 56 cases of meningioma. We found an association between high-grade meningiomas and high ET-1 expression levels (p=0.002). Moreover, we evaluated the potential angiogenic role of ET-1, finding an elevated microvessel count in tumours with high ET expression levels (p=0.004). ET-1 may contribute to meningioma growth by inducing formation of new blood vessels. The finding that ET-1 expression positively correlates with vascular endothelial growth factor (VEGF) expression in meningiomas (p=0.03) also supports the hypothesized modulating effect of ET-1 on angiogenesis. Thus, the influence of the ET system on the progression of meningiomas may occur through stimulation of VEGF. The association of ET-1 and meningioma represents a potential area for therapeutic intervention with selective ET inhibitors. Additional clinical studies will be needed before inhibitors can be incorporated in clinical practice.
SourceAvailable from: Bertrand AllardUniversité Paris-Sud 11, 01/2012, Degree: PhD
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ABSTRACT: Endothelin-1 (ET1) is a potent vasoconstrictor peptide with pro-mitogenic and pro-inflammatory properties and is therefore of interest in the development of endothelial dysfunction, endothelium-dependent flow-related remodeling, and hypertension-related remodeling. ET1 can be formed through cleavage of big ET1 by endothelin-converting enzyme (ECE) and neutral endopeptidase (NEP). We investigated whether the dual NEP/ECE inhibitor SOL1 improves resistance artery function and structure in 12 weeks old spontaneously hypertensive rats (SHRs) and whether arterial structural responses to decreased (-90%) or increased (+100%) blood flow are impaired in young SHRs. To this end two groups of SHRs received chronic 4-week treatment at two different time points (4-8 and 8-12 weeks) prior to the experiment. We compared in-vitro effects of cyclo-oxygenase inhibition (1 μmol/l indomethacine), nitric oxide synthase inhibition (100 μmol/l N(ω)-L-nitro arginine methyl ester), and stimulation of the endothelium by 0.001-10 μmol/l acetylcholine (ACh) in isolated third-order mesenteric arteries of SHRs and aged-matched Wistar-Kyoto (WKY) rats. SOL1 had no effect on blood pressure in SHRs or WKY rats. ACh caused biphasic effects in mesenteric arteries of SHRs. The contractile component (endothelium-derived contractile factor) was absent in WKY and abolished by acute indomethacin administration or chronic SOL1 treatment. Endothelium-derived nitric oxide-type responses did not differ in both strains and were not influenced by SOL1 treatment. Endothelium-derived hyperpolarizing factor-type responses were severely impaired in SHRs as compared to WKY rats and were normalized by chronic SOL1 treatment. In first-order mesenteric arteries, outward flow-induced remodeling was impaired in SHRs. Chronic SOL1 treatment did not restore this response. Thus chronic SOL1 treatment during the development of hypertension in SHRs has no effect on blood pressure but improves several aspects of endothelium-dependent vasomotor responses but not arterial remodeling.Journal of Hypertension 07/2012; 30(9):1799-808. DOI:10.1097/HJH.0b013e3283569c7a · 4.22 Impact Factor
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ABSTRACT: Chondrosarcoma is the second most common sarcoma in bone malignancy and is characterized by a high metastatic potential. Angiogenesis is essential for the cancer metastasis. Endothelin-1 (ET-1) has been implicated in tumor angiogenesis and metastasis. However, the relationship of ET-1 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells is mostly unknown. Here, we found that the expression of ET-1 and VEGF were correlated with tumor stage and were significantly higher than that in the normal cartilage. Exogenous ET-1 with chondrosarcoma cells promoted VEGF expression and subsequently increased migration and tube formation in endothelial progenitor cells. ET-1 increased VEGF expression and angiogenesis through ETAR, integrin-linked kinase (ILK), Akt and hypoxia-inducible factor-1α (HIF-1α) signaling cascades. Knockdown of ET-1 decreased VEGF expression and also abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. In addition, in the xenograft tumor angiogenesis model, knockdown of ET-1 significantly reduced tumor growth and tumor-associated angiogenesis. Taken together, these results indicate that ET-1 occurs through ETAR, ILK and Akt, which in turn activates HIF-1α, resulting in the activation of VEGF expression and contributing to the angiogenesis and tumor growth of human chondrosarcoma cells.Oncogene advance online publication, 15 April 2013; doi:10.1038/onc.2013.109.Oncogene 04/2013; DOI:10.1038/onc.2013.109 · 8.56 Impact Factor