Cardiovascular Disease Program, Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia.
Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
Clin Sci (Lond). 2022 May 13;136(9):675-694. doi: 10.1042/CS20220182.
Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a 'preeclampsia-like' syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study, we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis-inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low- or high-dose aspirin for 8 days (n=5-7/group). Our results demonstrated that prostacyclin (PGI2) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low- and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low- and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors.
血管内皮生长因子拮抗剂与癌症患者的血管生成抑制剂诱导包括高血压、蛋白尿和内皮素 (ET)-1 升高的“子痫前期样”综合征。已知环氧化酶 (COX) 抑制作用（如阿司匹林）可预防高危患者子痫前期的发生。在本研究中，我们假设阿司匹林治疗可预防血管生成抑制剂诱导的高血压和肾脏损伤的发生。我们的目的是比较低剂量（COX-1 抑制）和高剂量（双重 COX-1 和 COX-2 抑制）阿司匹林对啮齿动物血管生成抑制剂治疗期间血压、血管功能、氧化应激、ET-1 和前列腺素水平以及肾脏损伤的影响。为此，我们用载体、血管生成抑制剂（舒尼替尼）单独或与低剂量或高剂量阿司匹林联合治疗 Wistar Kyoto 大鼠 8 天（每组 5-7 只）。我们的结果表明，在血管生成抑制剂治疗期间，前列环素 (PGI2) 和 ET-1 增加，而血栓素 (TXA2) 不变。低剂量和高剂量阿司匹林均能显著减轻血管生成抑制剂诱导的高血压和血管超氧化物产生，但只有高剂量阿司匹林能预防白蛋白尿。虽然低剂量和高剂量阿司匹林均可降低循环 TXA2 和前列腺素 F2α 水平，但只有高剂量阿司匹林可降低循环和尿液 PGI2 水平。最后，阿司匹林治疗并未显著影响 ET-1 或血管功能。总之，我们的研究结果表明，前列腺素参与了血管生成抑制剂诱导的高血压和肾脏损伤的发生，靶向前列腺素途径可能是减轻与血管生成抑制剂相关的心血管和肾脏毒性的有效策略。
