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Acute vascular and cardiac effects of lenvatinib in mice
Dustin N Krüger1,2, Patrizia Pannucci3,4, Callan D Wesley5,6
1Laboratory 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. dustin.kruger@uantwerpen.be.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Vascular endothelial growth factor (VEGF) inhibitor lenvatinib causes hypertension and arterial stiffness in mice. While cardiac function recovers after washout, hypertension persists, suggesting complex cardiovascular effects.
Area of Science:
- Cardiovascular Pharmacology
- Oncology
- Angiogenesis Inhibition
Background:
- Tyrosine kinase inhibitors (TKIs) targeting VEGF receptor signaling are crucial in cancer therapy for inhibiting angiogenesis.
- VEGF inhibitors are associated with significant cardiovascular toxicities, particularly hypertension.
- Understanding the specific cardiovascular impacts of TKIs like lenvatinib is essential for patient safety.
Purpose of the Study:
- To investigate the short-term effects of the TKI lenvatinib on blood pressure, arterial stiffness, vascular reactivity, and cardiac function in a murine model.
- To identify potential mechanisms contributing to the cardiovascular toxicities observed with VEGF inhibition.
- To assess the reversibility of lenvatinib-induced cardiovascular changes after treatment cessation.
Main Methods:
- Male C57BL/6J mice were treated with lenvatinib (4 mg/kg/day) or control for 4 days.
- Blood pressure, arterial stiffness (pulse wave velocity), and cardiac function (echocardiography) were assessed.
- Ex vivo vascular reactivity of thoracic aortic segments was determined, including responses to ATP and nitric oxide.
- A 4-day washout period was included to evaluate recovery of cardiovascular parameters.
Main Results:
- Lenvatinib induced significant hypertension and increased arterial stiffness from day 2 of treatment.
- Cardiac function was impaired, with reduced left ventricular ejection fraction and dilation.
- Endothelial function and vascular smooth muscle cell reactivity to nitric oxide were not affected.
- ATP-mediated relaxation increased concentration-dependently, and cardiac adaptation/arterial stiffness recovered post-washout, though hypertension persisted.
Conclusions:
- Lenvatinib significantly impacts cardiovascular parameters, causing hypertension and arterial stiffness, with persistent hypertension after washout.
- The study highlights the complex interplay between VEGF inhibition and cardiovascular function, necessitating further research into lenvatinib's specific CV effects.
- A potential synergistic interaction between VEGF and ATP via P2Yx receptor signaling is proposed as a mechanism for enhanced vascular response.
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