Hutchinson-Gilford progeria syndrome (HGPS) is a rare disorder caused by a point mutation in the Lamin A gene that produces the protein progerin. Progerin toxicity leads to accelerated aging and death from cardiovascular disease. To elucidate the effects of progerin on endothelial cells, we prepared tissue-engineered blood vessels (viTEBVs) using induced pluripotent stem cell-derived smooth muscle cells (viSMCs) and endothelial cells (viECs) from HGPS patients. HGPS viECs aligned with flow but exhibited reduced flow-responsive gene expression and altered NOS3 levels. Relative to viTEBVs with healthy cells, HGPS viTEBVs showed reduced function and exhibited markers of cardiovascular disease associated with endothelium. HGPS viTEBVs exhibited a reduction in both vasoconstriction and vasodilation. Preparing viTEBVs with HGPS viECs and healthy viSMCs only reduced vasodilation. Furthermore, HGPS viECs produced VCAM1 and E-selectin protein in TEBVs with healthy or HGPS viSMCs. In summary, the viTEBV model has identified a role of the endothelium in HGPS.
Keywords: Hutchinson-Gilford progeria syndrome; induced pluripotent stem cells; microphysiological system; shear stress; smooth muscle cells; tissue-engineered blood vessel; vascular endothelium.
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