Abstract
The mammalian skeletal system shows sex differences in structure, functions, ageing and disease incidences. The role of blood vessels in physiological, regenerative and pathological bone functions indicates the requisite to understanding their sex specificity. Here, we find oestrogen regulates blood vessel physiology during pregnancy and menopause through oestrogen receptor alpha (ERα) and G-protein coupled oestrogen receptor-1 (Gper1) but not ERβ-dependent signalling in mice. Oestrogen regulates BECs' lipid use and promotes lipolysis of adipocytes and FA uptake from the microenvironment. Low oestrogen conditions skew endothelial FA metabolism to accumulate lipid peroxides (LPO), leading to vascular ageing. High ferrous ion levels in female BECs intensify LPO accumulation and accelerate the ageing process. Importantly, inhibiting LPO generation using liproxstatin-1 in aged mice significantly improved bone heath. Thus, our findings illustrate oestrogen's effects on BECs and suggest LPO targeting could be an efficient strategy to manage blood and bone health in females.