ORIGINAL RESEARCH article
Front. Physiol.
Sec. Vascular Physiology
Volume 16 - 2025 | doi: 10.3389/fphys.2025.1599339
This article is part of the Research TopicDecoding Vascular Aging: Unraveling the Enigma of Pathological Conditions & Pre-mature Vascular AgingView all 9 articles
Hutchinson Gilford Progeria Syndrome alters the endothelial genetic response to laminar shear stress
Provisionally accepted
- 1University Program in Genetics and Genomics, Duke University, Durham, United States
- 2Florida Institute of Technology, Melbourne, Florida, United States
- 3Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina, United States
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Hutchinson-Gilford Progeria Syndrome (HGPS) is a fatal, accelerated-aging disease caused by a mutation in the nuclear envelope protein Lamin A. The resulting mutant protein, progerin, accumulates on the nuclear envelope, causing nuclear blebbing, altered gene expression, and other cellular defects. The primary pathology of HGPS is atherosclerosis, leading to stroke or heart attack. Given that atherosclerosis begins with endothelial dysfunction in non-HGPS individuals, we examined whether the HGPS endothelium has an altered genetic response to shear stress, contributing to atherogenesis. We examined morphology and gene expression of HGPS and healthy iPSC-derived endothelial cells (viECs) after exposure to steady laminar shear stress (12 dynes/cm 2 for 24 hours) in a parallel-plate flow channel. We found that elongation in response to flow is impaired in HGPS viECs compared with healthy viECs. Differential expression (DE) analysis showed fewer significant differentially expressed genes and a lower magnitude of gene expression change after flow in HGPS compared with healthy viECs. Gene Set Enrichment Analysis identified differences in the gene sets altered by flow-induced DE, including Cholesterol Homeostasis, which was overrepresented in HGPS viECs. LGALS3, encoding the atherosclerosis marker galectin-3, was a main driver of this overrepresentation. RT-PCR confirmed LGALS3 as a shear-sensitive gene robustly upregulated in HGPS viECs compared with healthy viECs after flow. Treatment with an adenine base editor correcting the HGPS mutation restored LGALS3 expression to healthy levels. These observations indicate that HGPS ECs have an aberrant molecular response to atheroprotective shear stress, contributing to atherogenesis in HGPS patients.
Keywords: HGPS: Hutchinson-Gilford progeria syndrome, Endothelium, Shear stress (fluid), Atherosclerosis, LGALS3
Received: 24 Mar 2025; Accepted: 14 Jun 2025.
Copyright: © 2025 Kennedy, Carter and Truskey. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: George Truskey, Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, 27708-0281, North Carolina, United States
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