Updated project metadata. Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS patients, although the reason for such vulnerability remains poorly understood. In this work, we developed a chip formed from HGPS-SMCs that were generated from induced pluripotent stem cells (iPSCs) to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detached from the chip after a few days of culture; this process was mediated by the up-regulation of metalloprotease 13 (MMP13). Importantly, double mutant LmnaG609G/G609GMmp13-/- mice or LmnaG609G/G609GMmp13+/+ mice treated with a MMP inhibitor showed lower SMC loss in the aortic arch than controls. MMP13 up-regulation appears to be mediated by the up-regulation of heparan sulfate, a glycocalyx component. Our results offer a new platform for developing treatments for HGPS patients that may complement previous pre-clinical and clinical treatments.