Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow, UK.
Beatson West of Scotland Cancer Centre, Glasgow, UK.
Cardiovasc Res. 2019 Apr 15;115(5):978-988. doi: 10.1093/cvr/cvz021.
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.
血管内皮生长因子通路抑制剂（VEGFi）作为抗血管生成药物用于治疗癌症，其通过未知的分子机制与心血管毒性相关。内皮细胞衍生的微颗粒（ECMPs）是内皮损伤的生物标志物，并且具有功能活性，因为它们影响下游靶细胞信号转导和功能。我们质疑在接受 VEGFi 治疗的癌症患者中，微颗粒（MP）状态是否发生改变，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）治疗前后的癌症患者中分离血浆 MPs。用分离的 MPs（106 MPs/mL）刺激人主动脉内皮细胞（HAEC）。通过流式细胞术评估 MPs 的特征。接受 VEGFi 治疗的患者血浆 ECMP 水平显著升高。暴露于治疗后 VEGFi 的 ECMP 的内皮细胞诱导前原 ET-1 mRNA 表达增加，这与在受 vatalanib（VEGFi）刺激的 HAEC 中内皮素-1（ET-1）产生增加相吻合。治疗后 MPs 增加了 HAEC 中活性氧的产生，ETA（BQ123）和 ETB（BQ788）受体阻滞剂可减弱这些作用。治疗后 MPs 还增加了内皮型一氧化氮合酶（eNOS）抑制性位点的磷酸化，减少了 NO，并增加了 HAEC 中的 ONOO-水平，这些反应可被 ETB 受体阻断剂抑制。此外，暴露于治疗后 MPs 的 HAEC 中促炎介质的基因表达增加，这些反应可被 BQ123 和 BQ788 抑制。我们的研究结果定义了一种新的分子机制，涉及微颗粒、ET-1 系统和内皮细胞促炎和氧化还原信号之间的相互作用，这可能与 VEGFi 抗癌治疗相关的心血管毒性和高血压有关。新的和值得注意的是：我们的新数据将 MPs 确定为 VEGFi 诱导的内皮损伤的生物标志物，并且是 ET-1 敏感的氧化还原调节的促炎信号在内皮效应细胞中的重要介质，这些过程可能导致接受 VEGFi 治疗的癌症患者发生心血管毒性。
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