Engineering etiology-aligned in vitro models of human vessels

Vascular diseases remain a major global health burden, yet traditional animal models often fail to capture the human-specific mechanisms that drive disease progression. Recent policy shifts, including the FDA Modernization Act and the NIH's transition away from animal-only studies, have intensified the need for human-relevant vascular platforms. This review introduces an etiology-to-model framework that maps six principal classes of vascular disease, including congenital, metabolic, neoplastic, inflammatory, degenerative, and risk factor-induced, to the in vitro systems best equipped to reproduce their defining microenvironmental disturbances. We evaluate how 2D assays, organoids, organ-on-chip platforms, tissue-engineered grafts, and bioprinted vessels each recapitulate distinct structural, cellular, and hemodynamic features of human pathology. We argue that the central challenge is no longer the lack of advanced tools, but the need to validate models against disease-specific benchmarks and integrate biological complexity without compromising reproducibility. By embedding disease etiology into model design, this framework provides a foundation for developing predictive vascular platforms that accelerate mechanistic insight and support precision therapy development.