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Microparticles from vascular endothelial growth factor pathway inhibitor-treated cancer patients mediate endothelial cell injury

机译:血管内皮生长因子途径抑制剂治疗的癌症患者的微粒介导内皮细胞损伤

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摘要

Vascular endothelial growth factor pathway inhibitors (VEGFi), used as anti-angiogenic drugs to treat cancer are associated with cardiovascular toxicities through unknown molecular mechanisms. Endothelial cell-derived microparticles (ECMPs) are biomarkers of endothelial injury and are also functionally active since they influence downstream target cell signalling and function. We questioned whether microparticle (MP) status is altered in cancer patients treated with VEGFi and whether they influence endothelial cell function associated with vascular dysfunction. Plasma MPs were isolated from cancer patients before and after treatment with VEGFi (pazopanib, sunitinib, or sorafenib). Human aortic endothelial cells (HAECs) were stimulated with isolated MPs (106 MPs/mL). Microparticle characterization was assessed by flow cytometry. Patients treated with VEGFi had significantly increased levels of plasma ECMP. Endothelial cells exposed to post-VEGFi treatment ECMPs induced an increase in pre-pro-ET-1 mRNA expression, corroborating the increase in endothelin-1 (ET-1) production in HAEC stimulated with vatalanib (VEGFi). Post-VEGFi treatment MPs increased generation of reactive oxygen species in HAEC, effects attenuated by ETA (BQ123) and ETB (BQ788) receptor blockers. VEGFi post-treatment MPs also increased phosphorylation of the inhibitory site of endothelial nitric oxide synthase (eNOS), decreased nitric oxide (NO), and increased ONOO levels in HAEC, responses inhibited by ETB receptor blockade. Additionally, gene expression of proinflammatory mediators was increased in HAEC exposed to post-treatment MPs, effects inhibited by BQ123 and BQ788. Our findings define novel molecular mechanism involving interplay between microparticles, the ET-1 system and endothelial cell pro-inflammatory and redox signalling, which may be important in cardiovascular toxicity and hypertension associated with VEGFi anti-cancer treatment. New and noteworthy: our novel data identify MPs as biomarkers of VEGFi-induced endothelial injury and important mediators of ET-1-sensitive redox-regulated pro-inflammatory signalling in effector endothelial cells, processes that may contribute to cardiovascular toxicity in VEGFi-treated cancer patients.
机译:用作血管生成药物治疗癌症的血管内皮生长因子途径抑制剂(VEGFi)通过未知的分子机制与心血管毒性相关。内皮细胞来源的微粒(ECMP)是内皮损伤的生物标志物,并且在功能上也具有活性,因为它们会影响下游靶细胞的信号传导和功能。我们质疑在接受VEGFi治疗的癌症患者中微粒(MP)状态是否改变,以及它们是否影响与血管功能障碍相关的内皮细胞功能。从接受VEGFi(帕唑帕尼,舒尼替尼或索拉非尼)治疗的癌症患者中分离血浆MP。用分离的MPs(10 6 MPs / mL)刺激人主动脉内皮细胞(HAEC)。通过流式细胞术评估微粒表征。接受VEGFi治疗的患者血浆ECMP水平明显升高。暴露于VEGFi处理后ECMP的内皮细胞诱导了ET-1前原mRNA表达的增加,从而证实了受vatalanib(VEGFi)刺激的HAEC中内皮素1(ET-1)产生的增加。 VEGFi处理后的MPs增加了HAEC中活性氧的生成,其作用被ETA(BQ123)和ETB(BQ788)受体阻滞剂减弱。 VEGFi处理后的MPs还增加了内皮一氧化氮合酶(eNOS)抑制位点的磷酸化,降低了一氧化氮(NO),并增加了HAEC中的ONOO -水平,并受到ETB受体阻滞的抑制。此外,暴露于治疗后MPs的HAEC中促炎性介质的基因表达增加,其作用被BQ123和BQ788抑制。我们的发现确定了涉及微粒,ET-1系统与内皮细胞促炎和氧化还原信号之间相互作用的新型分子机制,这可能在心血管毒性和与VEGFi抗癌治疗相关的高血压中起重要作用。新的和值得注意的:我们的新数据确定MPs是VEGFi诱导的内皮损伤的生物标志物,并且是效应子内皮细胞中ET-1敏感的氧化还原调节促炎性信号传导的重要介质,这些过程可能有助于VEGFi治疗的癌症的心血管毒性耐心。

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