Abstract
BACKGROUND: Breast cancer chemotherapy increases cardiovascular (CV) risk, particularly in postmenopausal women. Although vascular damage, endothelial dysfunction, and oxidative stress are implicated, the role of menopausal status in vascular mechanisms of increased CV risk remains unknown. Accordingly, we investigated whether estrogens protect premenopausal women from neoadjuvant chemotherapy (TAC protocol)-induced endothelial dysfunction, focusing on the vascular effects of docetaxel. This is the first study to assess how menopausal status affects vascular responses to chemotherapy. OBJECTIVES: The main objective was to elucidate the pathophysiologic mechanisms by which TAC precipitates vascular dysfunction, with an emphasis on the influence of menopausal status. METHODS: Vascular function, oxidative stress, and molecular pathways were evaluated in arterial segments from cancer-free breast tissue of premenopausal and postmenopausal women undergoing surgery with or without prior TAC. Complementary mechanistic studies were conducted in ovariectomized and control female C57BL/6J mice treated with docetaxel or placebo. RESULTS: TAC-induced endothelial dysfunction, marked by reduced nitric oxide bioavailability, was observed in vessels from postmenopausal women, whereas premenopausal women were protected. The vessels of premenopausal women also resisted TAC-induced oxidative stress, showing significantly lower superoxide and hydrogen peroxide production as well as NOX4 NADPH-oxidase expression compared with their postmenopausal counterparts. No differences were noted between premenopausal and postmenopausal women in the non-TAC groups. At the molecular level, TAC resulted in lower inhibitory phosphorylation of endothelial nitric oxide synthase (eNOS) at threonine-495 and reduced rho-kinase activity in premenopausal women. In mice, docetaxel caused endothelial dysfunction, molecular changes, and hypertension only in ovariectomized animals, with no such effects in age-matched nonovariectomized controls. CONCLUSIONS: TAC-induced vascular dysfunction seen in breast cancer survivors is absent in premenopausal women, likely owing to estrogen-mediated protection against oxidative stress and eNOS inhibition.