Endothelial cell heterogeneity drives angiogenesis in endometriosis: mechanisms and emerging organoid-based models

Endometriosis (EMs) is characterized by the establishment and persistence of ectopic lesions, a process fundamentally dependent on aberrant angiogenesis. Endothelial cells (ECs) play a central role in this process; however, accumulating evidence indicates that ECs are not a homogeneous population but comprise multiple subtypes with distinct molecular signatures and functional states, including quiescent, proliferative, hormone-responsive and inflammation-associated phenotypes. The initiation and maintenance of pathological angiogenesis in EMs are coordinately regulated by hormonal signaling, inflammatory responses and immune modulation, which collectively determine vascular remodeling and lesion sustainability. Despite significant advances, mechanistic insights into EMs-associated angiogenesis have been limited by the lack of physiologically relevant experimental models. Conventional two-dimensional culture systems fail to recapitulate the complex three-dimensional cellular interactions, whereas animal models are constrained by interspecies differences. Recent progress in stem cell biology, extracellular matrix (ECM) engineering and microfluidic technologies has enabled the development of organoid-based platforms that more faithfully reconstruct the EMs microenvironment. When integrated with functional biomaterials possessing tunable mechanical properties and bioactivity, these systems allow precise modulation of endothelial behaviors, including proliferation, migration and lumen formation, through controlled delivery of angiogenic cues. In this Review, we summarize recent advances in biomaterial-supported organoid systems for dissecting endothelial cell heterogeneity and its contribution to aberrant angiogenesis in EMs. We further discuss their emerging roles in mechanistic studies and the development of targeted therapeutic strategies.