Reprogramming the Aging Type H Vascular Niche via Myeloid Angiogenic Cell-Derived Extracellular Vesicles: Mechanisms,...

Age-related osteoporosis is characterized by the simultaneous loss of bone mass and the regression of CD31^hiEmcn^hi (Type H) vessels, a specialized capillary subtype that functionally couples angiogenesis with osteogenesis. The endothelial progenitor cell (EPC) compartment, comprising myeloid angiogenic cells (MACs) and endothelial colony-forming cells (ECFCs), contributes to the maintenance of this vascular niche; however, its regenerative potential declines with age, partly as a consequence of cellular senescence and acquisition of the senescence-associated secretory phenotype (SASP). Given the clinical hurdles of conventional cell transplantation, therapeutic development has shifted toward cell-free strategies based on the MAC/ECFC secretome, particularly extracellular vesicles (EVs). In this review, we clarify the distinction between MACs and ECFCs to resolve historical conceptual ambiguities, and examine how their paracrine cues regulate angiogenic-osteogenic coupling. We then synthesize current evidence on endothelial EV cargo and discuss how aging remodels vesicle composition and function to drive vascular-bone uncoupling. Beyond existing reviews on EPC-EVs, Type H vessels, or EV-based bone regeneration, we add a protocol-driven re-annotation and explicitly distinguish bone-related studies methodologically compatible with MAC-derived EVs from adjacent evidence using other endothelial cell sources and mechanistic support from non-skeletal models. Finally, we compare bioengineering strategies, including preconditioning, precision cargo engineering, surface targeting, and scaffold/hydrogel delivery, aimed at correcting senescence-associated cargo liabilities and improving translational readiness.