Characterization of anti-cancer therapy-induced microvascular dysfunction in breast cancer patients with proof-of-concept of targeted intervention

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Abstract

BACKGROUND. Cardiotoxicity is a major complication of anti-cancer therapy (CTx); yet, the impact of CTx on the human microcirculation is not well defined. This study evaluated the impact of CTx on microvascular function in breast cancer patients. METHODS. Endothelial function and angiogenic potential were assessed in arterioles and adipose biopsies obtained from breast cancer patients before, during, and after CTx (longitudinal and cross-sectional) and in healthy arterioles exposed to doxorubicin (Dox), trastuzumab (TZM), or paclitaxel (PTX) ex vivo. Conditioned media containing VEGF-B protein was used to test feasibility of a targeted intervention. RESULTS. Patients treated with Dox and/or TZM in vivo developed profound microvascular endothelial dysfunction that persisted for ≥9 months after treatment cessation. Angiogenic potential was reduced during CTx and recovered within one month after cessation. Gene expression related to angiogenesis and inflammation changed over the course of clinical treatment. Isolated adipose arterioles from healthy donors developed endothelial dysfunction when exposed to Dox or TZM ex vivo. In contrast, paclitaxel (PTX), which poses minimal cardiovascular risk, had no impact on vasomotor function. Ex vivo exposure to Dox or PTX suppressed angiogenic potential, whereas TZM had no effect. Treatment with VEGF-B protein preserved endothelial function in healthy arterioles exposed to Dox or TZM ex vivo. CONCLUSION. Breast cancer patients undergoing treatment with Dox and/or TZM develop prolonged microvascular endothelial dysfunction that is recapitulated in healthy arterioles exposed to Dox or TZM ex vivo. Targeted intervention with VEGF-B protects against direct Dox- or TZM-induced vascular toxicity in human arterioles ex vivo. FUNDING. National Institutes of Health grant R01 HL133029, HL173549 (AMB). National Institutes of Health grant T32 HL134643 (JDT, STH). American Heart Association grant SFRN847970 (AMB, DDG). We Care Foundation Grant (AMB, ALK). Medical College of Wisconsin Cardiovascular Center Pre-PPG Grant (AMB). Advancing a Healthier Wisconsin – Redox Biology Grant (AMB). Jenny and Antti Wihuri Foundation (RMK).

Authors

Janée D. Terwoord, Laura E. Norwood Toro, Shelby N. Hader, Stephen T. Hammond, Joseph C. Hockenberry, Jasmine Linn, Ibrahim Y. Vazirabad, Amanda L. Kong, Alison J. Kriegel, Ziqing Liu, Riikka M. Kivelä, Gillian Murtagh, David D. Gutterman, Andreas M. Beyer