Krüger Dustin N, Pannucci Patrizia, Wesley Callan D, Neutel Cedric H G, Martinet Wim, De Meyer Guido R Y, Hill Stephen J, Woolard Jeanette, Franssen Constantijn, Guns Pieter-Jan
Laboratory of Physiopharmacology, Faculty of Medicine and Health Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Campus Drie Eiken, University of Antwerp, Universiteitsplein 1, Antwerp, B-2610, Belgium.
Infla-Med Centre of Excellence of the University of Antwerp, Antwerp, Belgium.
Cardiooncology. 2025 Feb 11;11(1):14. doi: 10.1186/s40959-025-00307-8.
Tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) receptor signalling are used in cancer therapy to inhibit angiogenesis. Unfortunately, VEGF inhibitors are known to induce severe hypertension in patients. This study aimed to elucidate the impact of the TKI lenvatinib on blood pressure, arterial stiffness, vascular reactivity, as well as cardiac function in a short-term murine model to shed light on potential contributors to cardiovascular (CV) toxicities associated with VEGF inhibition.
Male C57BL/6J mice were randomly divided into 2 cohorts, either treated for 4 days with lenvatinib 4 mg/kg/day or 40% hydroxypropyl β-cyclodextrin as control. In an additional study, mice were subjected to a 4-day treatment followed by a 4-day wash-out, with echocardiography and blood pressure measurements performed on day 2 and 7. Subsequently, ex vivo vascular reactivity of thoracic aortic segments was determined.
Lenvatinib induced hypertension and arterial stiffness (i.e., increased pulse wave velocity), starting from day 2 of treatment. Further, left ventricular ejection fraction was reduced and the ventricle dilated upon treatment. Lenvatinib induced neither endothelial dysfunction nor impaired vascular smooth muscle cell reactivity to nitric oxide (NO). Interestingly, lenvatinib demonstrated a concentration-dependent increase in ATP-mediated relaxation. In addition, after the 4-day wash-out period, lenvatinib-treated mice did not show complete remission of hypertension. However, arterial stiffness, ATP-mediated relaxation and cardiac adaptation were recovered.
This comprehensive investigation provides valuable insights into the interplay between VEGF inhibition, vascular function and cardiac outcomes, emphasising the need for nuanced understanding and further exploration of the differential effects of lenvatinib on the CV system. Additionally, the study proposes a synergistic formation between VEGF and ATP, indicating an enhanced response via P2Yx receptor signalling.
靶向血管内皮生长因子（VEGF）受体信号通路的酪氨酸激酶抑制剂（TKIs）用于癌症治疗以抑制血管生成。遗憾的是，已知VEGF抑制剂会在患者中诱发严重高血压。本研究旨在阐明TKI乐伐替尼对短期小鼠模型血压、动脉僵硬度、血管反应性以及心脏功能的影响，以揭示与VEGF抑制相关的心血管（CV）毒性的潜在因素。
将雄性C57BL/6J小鼠随机分为2组，一组用4mg/kg/天的乐伐替尼治疗4天，另一组用40%羟丙基β-环糊精作为对照。在另一项研究中，小鼠接受4天治疗，随后进行4天洗脱期，在第2天和第7天进行超声心动图和血压测量。随后，测定胸主动脉段的离体血管反应性。
从治疗第2天起，乐伐替尼诱发高血压和动脉僵硬度（即脉搏波速度增加）。此外，治疗后左心室射血分数降低且心室扩张。乐伐替尼既未诱导内皮功能障碍，也未损害血管平滑肌细胞对一氧化氮（NO）的反应性。有趣的是，乐伐替尼显示出ATP介导的舒张呈浓度依赖性增加。此外，在4天洗脱期后，乐伐替尼治疗的小鼠高血压未完全缓解。然而，动脉僵硬度、ATP介导的舒张和心脏适应性恢复。
这项全面研究为VEGF抑制、血管功能和心脏结局之间的相互作用提供了有价值的见解，强调需要对乐伐替尼对心血管系统的不同影响进行细致入微的理解和进一步探索。此外，该研究提出VEGF和ATP之间形成协同作用，表明通过P2Yx受体信号通路增强反应。
