Mechanometabolic endothelial senescence as a translational framework for cardiometabolic vascular disease and vascular ageing.

Cardiometabolic vascular disease (CMVD) is used in this Review as an operational umbrella for vascular injury arising from interacting metabolic, renal and cardiovascular stress, rather than as a universally standardised diagnosis. We examine mechanometabolic endothelial senescence as a framework linking local haemodynamic vulnerability with systemic cardiometabolic load. Evidence from human vascular tissue, clinical vascular-function studies, animal models, flow-controlled systems and endothelial-cell experiments indicates that low or oscillatory shear, matrix stiffness, hyperglycaemia, dyslipidaemia, uraemic and hepatic stress, inflammation and oxidative injury can converge on DNA-damage responses, p53/p21 and p16/pRB signalling, NAD⁺-sirtuin decline, mitochondrial dysfunction, metabolic rewiring and chromatin regulation. Biological sex modifies this framework: endothelial function declines across the menopause transition, whereas direct human arterial evidence suggests that senescence-associated endothelial dysfunction may differ between women and men; however, sex-disaggregated mechanistic data remain sparse. Clinically, flow-mediated dilatation, carotid-femoral pulse-wave velocity, coronary flow reserve and the index of microcirculatory resistance provide compartment-specific functional anchors, but none is a direct senescence assay. Evidence in heart failure with preserved ejection fraction, chronic kidney disease and metabolic dysfunction-associated steatotic liver disease remains heterogeneous and is strongest in preclinical or mixed translational studies. We therefore propose a staged validation strategy combining endothelial identity, convergent senescence markers, circulating-cell or extracellular-vesicle measures, vascular function and organ-specific outcomes. Mechanometabolic endothelial senescence is best viewed as a context-dependent disease amplifier and testable translational model, not a universal primary cause.