Characterization of anticancer therapy-induced microvascular dysfunction in patients with breast cancer supports...

BACKGROUNDCardiotoxicity is a major complication of anticancer therapy (CTx); however, the effect of CTx on the microcirculation is not well defined. This study evaluated the effect of CTx on microvascular function in patients with breast cancer (PwBC).METHODSEndothelial function and angiogenic potential were assessed in arterioles and adipose biopsies obtained from PwBC undergoing CTx (longitudinal and cross-sectional) and in healthy arterioles exposed to doxorubicin (Dox), trastuzumab (TZM), or paclitaxel (PTX) ex vivo. VEGF-B protein was used to test feasibility of targeted intervention.RESULTSPwBC treated with Dox and/or TZM developed profound microvascular endothelial dysfunction that persisted for ≥ 9 months after treatment cessation. Angiogenic potential was reduced during CTx and recovered within 1 month. Gene expression related to angiogenesis and inflammation changed over the course of clinical treatment. Adipose arterioles from healthy donors developed endothelial dysfunction when exposed to Dox or TZM ex vivo. PTX, which poses minimal cardiovascular risk, had no effect on vasomotor function. Ex vivo exposure to Dox or PTX suppressed angiogenic potential, whereas TZM had no effect. VEGF-B protein preserved endothelial function in arterioles exposed to Dox or TZM ex vivo.CONCLUSIONPwBC 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.FUNDINGNIH, American Heart Association, WeCare Foundation, Medical College of Wisconsin, Advancing a Healthier Wisconsin, Jenny and Antti Wihuri Foundation.