Breast Cancer Chemotherapy Induces Vascular Dysfunction and Hypertension

Cardiovascular disease is the major cause of mortality in breast cancer survivors. Chemotherapy contributes to this risk. Accordingly, we aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel targets for pharmacological intervention. We studied human mammary arteries from women who had undergone NACT for breast cancer using docetaxel, doxorubicin and cyclophosphamide and women with no history of such treatment matched for key clinical parameters. Mechanisms were further explored in wild-type and Nox4-/- mice and human microvascular endothelial cells. Endothelium-dependent relaxation was severely impaired in patients after NACT, while endothelium-independent responses remain normal. This was mimicked by 24-hour exposure of arteries to NACT agents ex vivo. When applied individually, only docetaxel significantly impaired endothelial function in human vessels. Overall design: Vascular rings (mammary artery) from 6 female patients, with no history of NACT, were incubated with 100 nM docetaxel (Cayman Chemicals) and vehicle (solvent) as a control (paired design). The vessels were incubated in a buffer containing: Hank's Balanced Salt Solution (HBSS; Gibco), 20 mM Hepes (Gibco) and gentamicin with glutamine in an incubator at 37°C in a humidified atmosphere for 24 hours. After incubation, vascular function was measured or rings were placed in RNAlater (Ambion) for gene expression and RNAseq studies. RNA was isolated using Direct-zol RNA MiniPrep kit (Zymo Research) and treated with DNase I. RNAseq profiling was performed by Genewiz (United Kingdom).