Lenvatinib halts aortic aneurysm growth by restoring smooth muscle cell contractility.

Albert Busch,Jessica Pauli,Armin Wiegering,Judith Reiser,Johannes Fischer,Christoph Otto,Valentina Paloschi,Joy Roy,Sonja Bleichert,Julia Werner,Ekaterina Chernogubova,Matthias Trenner,Christine Brostjan,Christoph Knappich,Hans-Henning Eckstein,Hanna Winter,Greg Winski,Lars Maegdefessel,Susanne Metschl

doi:10.1172/jci.insight.140364

Abstract

Abdominal aortic aneurysm (AAA) is a disease with high morbidity and mortality, especially when ruptured. The rationale of this study was to evaluate the repurposing of lenvatinib, a multi–tyrosine kinase inhibitor, in limiting experimental AAA growth targeting vascular smooth muscle cells (VSMCs) and angiogenesis. We applied systemic and local lenvatinib treatment to elastase-induced murine aortic aneurysms, and RNA profiling identified myosin heavy chain 11 (Myh11) as the most deregulated transcript. Daily oral treatment substantially reduced aneurysm formation in 2 independent mouse models. In addition, a large animal aneurysm model in hypercholesterolemic low-density lipoprotein receptor–knockout (LDLR–/–) Yucatan minipigs was applied to endovascularly deliver lenvatinib via drug-eluting balloons (DEBs). Here, a single local endovascular delivery blocked AAA progression successfully compared with a DEB-delivered control treatment. Reduced VSMC proliferation and a restored contractile phenotype were observed in animal tissues (murine and porcine), as well as AAA patient-derived cells. Apart from increasing MYH11 levels, lenvatinib reduced downstream ERK signaling. Hence, lenvatinib is a promising therapy to limit aortic aneurysm expansion upon local endovascular delivery. The tyrosine kinase inhibitor was able to positively affect pathways of key relevance to human AAA disease, even in a potentially new local delivery using DEBs.

Highlights

Abdominal aortic aneurysm (AAA) is a diameter enlargement of the infrarenal aorta by 1.5-fold or bigger
Treatment started 7 days after aneurysm induction when a small AAA had already developed upon PPE-induced AAAs (PPE) instillation [7]
MYH11 is an established marker for the contractile phenotype of vascular smooth muscle cells (VSMCs) and known to be decreased in AAA compared with nonaneurysmal controls [12]

Summary

Introduction

AAA is a diameter enlargement of the infrarenal aorta by 1.5-fold or bigger. Due to the risk of rupture, aneurysm disease is among the leading causes of death in Western countries. Risk factors include arterial hypertension, hyperlipidemia, male sex, family history, and smoking. The pathogenesis of AAA is not yet fully understood, and the mechanisms triggering disease development and progression remain unclear. The initial event and site-specific occurrence of aneurysm formation are largely elusive, prompting recent interest into better experimental models and research in general [1]. Some crucial mechanisms have been well characterized, including local wall stress alteration, enzymatic and mechanical intraluminal thrombus formation, proteolytic imbalance, and a humoral immune answer as a possible repair or healing mechanism [3]. Phenotypic changes in VSMCs and the hypoxic micromilieu that involves angiogenesis in the aortic media have gained some attention and experimental therapies aimed at addressing them [4]

Methods

Results

Conclusion