Bioengineered iPSC Vessels Recapitulate Human Vascular Physiological Function and Aging Phenotypes

Abstract

Vascular aging contributes to multisystem diseases and limits health span. Although various animal models have contributed to aging research, their vasculatures poorly recapitulate human physiology. Even existing tissue-engineered blood vessels fail to mimic human vascular function and pathology, hindering translational advances in vascular aging studies. Here, we present a novel human physiological vascular model fabricated via the unique molding-induced circumferential alignment of human induced pluripotent stem cell (iPSC)-derived vascular smooth muscle cells with luminally seeded endothelial cells. This architecture enabled dynamic vasodiameter changes in response to vasoactive stimuli, including hormones and intraluminal pressure. Using iPSCs from a patient with Werner syndrome, the model recapitulated aging-associated phenotypes, such as hypercontractility and increased vascular compliance, possibly due to impaired nitric oxide bioavailability. Transcriptomic and metabolomic analyses revealed age-related dysregulation consistent with vascular senescence. As a key advantage of the vasculature, spatial transcriptomic analysis demonstrated upregulation of the aging marker CDKN1A near the lumen and downregulation of COL6A1 and TPM1 throughout the vessel. Treatment with mitochonic acid 5, a mitochondria-targeted compound, significantly reversed the aging phenotypes. These findings demonstrate that our engineered vascular model recapitulates key aspects of human vascular properties and provides a platform for mechanistic studies of vascular aging and drug discovery aimed at extending health span.