Age- and sex-dependent bone marrow adiposity and distinct transcriptional trajectories in endothelial subtypes

The bone marrow vascular niche is a highly specialized network essential for governing the maintenance, differentiation, and mobilization of tissue-resident stem cells, notably hematopoietic stem cells. With ageing, the spatial organization and functional integrity of this vasculature undergo significant decline. While prior studies have characterized broad vessel types into arterioles, sinusoids, and transitional capillaries, the molecular heterogeneity and spatial structural remodeling of the bone marrow endothelium during ageing remain poorly defined. Through a multi-modal analysis of murine tibial bone marrow across the lifespan, we demonstrate that vascular remodeling is a spatially heterogeneous process characterized by profound sex-specific differences. Structurally, ageing precipitated significant bone marrow adiposity and a contraction of the microvascular network, changes that were markedly more pronounced in females. At the single-cell level, we identified sinusoidal endothelial cells (SECs) as a uniquely vulnerable population exhibiting age-related molecular deterioration. These alterations were driven by a specific bioenergetic collapse, marked by the downregulation of mitochondrial genes and critical HSC-retention factors. Our results reveal that vascular ageing is not a uniform decline but a subtype-specific mosaic of failure. The selective dysfunction and bioenergetic collapse of SECs emerge as a central driver of niche degradation, identifying this population as a key therapeutic target to combat age-related hematopoietic dysfunction.