Angiogenesis is essential for tissue growth and repair, but it also contributes to diseases such as cancer. Despite its central role in health and disease, progress in angiogenesis research and anti-angiogenic drug development has been limited by the lack of in vitro models that capture the cellular complexity, three-dimensional structure, and dynamic remodeling of living tissues while remaining practical for screening. Commonly used endothelial monolayer and aortic ring assays are informative, but they often fall short when researchers need physiologically relevant and scalable systems for drug discovery.
In a study published in Science Bulletin , Professor Hua Zhang’s team at China Agricultural University reports that growing ovarian follicles can function as natural microphysiological systems for angiogenesis. The researchers show that each follicle contains the essential cellular and molecular components required for active vascular growth, including endothelial cells, pericytes, extracellular matrix, and VEGFA–VEGFR2 signaling. Notably, each follicle functions as a relatively self-consistent unit that supports both its own development and active angiogenesis in surrounding vessels. Building on this insight, the team established an ovarian follicle-based angiogenesis microphysiological system (OF-AMPS) that enables direct visualization and quantitative analysis of vascular remodeling.
The platform does not require exogenous VEGF. Upon isolation and culture, ovarian follicles rapidly form complex three-dimensional vascular networks within 24 hours, while preserving key features of the native tissue microenvironment. Each mouse yields approximately 50 qualified assay units, allowing the system to balance physiological relevance with practical throughput. In addition, OF-AMPS is compatible with routine fluorescence microscopy as well as high-resolution confocal imaging, making it suitable for both high-content screening and mechanistic studies.
To assess its functional performance, the researchers examined whether OF-AMPS could distinguish true anti-angiogenic effects from nonspecific cytotoxicity. In this system, axitinib and sunitinib exhibited clear dose-dependent inhibition of angiogenesis, while their effective concentrations—as well as that of imatinib—did not impair follicle growth. In contrast, vincristine suppressed vascular expansion but also compromised follicular viability. This dual readout enables simultaneous evaluation of vascular inhibition and tissue integrity, thereby improving the reliability of screening outcomes.
The team further evaluated the platform’s utility for drug discovery by screening a commercial library of 406 small molecules with predicted anti-angiogenic activity. After two rounds of screening, 22 hit compounds were identified that selectively or dose-dependently inhibited angiogenesis without affecting follicular viability. Notably, more than 80% of these hits had already entered clinical development, supporting the predictive power of the system. Among them, Ki8751 emerged as a particularly promising candidate, showing strong anti-angiogenic activity without compromising follicle growth.
The researchers then validated these findings in vivo. In a mouse ovarian angiogenesis model, Ki8751 reduced vascular density to a level comparable to axitinib, whereas the inactive analogue ZM306416 showed no significant effect. In a human hepatocellular carcinoma xenograft model, Ki8751 also markedly suppressed tumor growth, with efficacy similar to axitinib. These results highlight the potential of OF-AMPS to identify anti-angiogenic compounds with meaningful in vivo activity.
Overall, OF-AMPS provides a physiologically relevant yet experimentally accessible three-dimensional model for angiogenesis research. By integrating native mammalian tissue architecture with rapid imaging and practical screening capacity, this ovarian follicle-based system offers a powerful platform for both fundamental studies of vascular remodeling and the discovery of anti-angiogenic therapies.
As the corresponding author, Dr. Hua Zhang noted, “We believe OF-AMPS can be a valuable tool for anti-angiogenic drug discovery. More importantly, we hope this work will encourage researchers and clinicians to look beyond the ovary’s traditional role as a reproductive organ and recognize its broader value as a powerful model for studying fundamental developmental processes.”
Science Bulletin
Experimental study