# Investigation of the molecular mechanisms of vascular endothelial dysfunction in Hutchinson-Gilford Progeria Syndrome through in vitro 2D and 3D models

> **NIH NIH R36** · UNIV OF MARYLAND, COLLEGE PARK · 2021 · $70,019

## Abstract

Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare, genetic disorder with features of
accelerated aging. The majority of HGPS cases caused by a de novo point mutation in the LMNA
gene (c.1824C > T; p.G608G) that results in progerin, a toxic lamin A protein variant. Children
with the disease mostly die from coronary artery diseases or strokes at an average age of 14.6
years. Endothelial dysfunction is a key contributor to the cardiovascular pathobiology as the
endothelium maintains vascular homeostasis and vascular tone by activating eNOS responsible
for nitric oxide (NO) production. Perturbation of eNOS activity causes many diseases including
atherosclerosis. Despite the vast knowledge of endothelial dysfunction in the pathogenesis of
cardiovascular disease, very little known about the role of progerin in the disruption of endothelial
cell function in HGPS. Furthermore, there is accumulated evidence about the role of progerin in
many aspects of generalized aging and cardiovascular health. Particularly, the atherosclerotic
plaques in HGPS are similar to those found in aging individuals. Moreover, vascular stiffening in
HGPS is much like that seen on normal aging that manifested in both populations by increased
pulse wave velocity.
Using human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs), I demonstrated
the reduction of endothelial nitric oxide synthase (eNOS) expression level and activity in HGPS
ECs compared to their normal controls. Consequently, the depletion of nitric oxide bioavailability
in HGPS ECs both in static and fluidic culture conditions. Remarkably, iPSC-derived HGPS ECs
exhibited eNOS dependent functional defects in forming microvascular networks that validated
through over-expression of progerin in healthy human umbilical vein endothelial cells (HUVECs).
I also found that Adenine Base Editor (ABEmax) that mediates the conversion of A×T to G×C in
genomic DNA efficiently corrected the HGPS mutation, and the progerin expression was
significantly reduced to the basal level. In addition, ABEmax rescued the nuclear blebbing
phenotype of the HGPS iPSC-ECs. Thus, the study provides valuable insights into HGPS
cardiovascular pathology and cardiovascular diseases associated with normal aging, and may
lead to novel strategies to treat cardiovascular disease in HGPS.

## Key facts

- **NIH application ID:** 10107973
- **Project number:** 1R36AG070573-01
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Yantenew G Gete
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $70,019
- **Award type:** 1
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10107973

## Citation

> US National Institutes of Health, RePORTER application 10107973, Investigation of the molecular mechanisms of vascular endothelial dysfunction in Hutchinson-Gilford Progeria Syndrome through in vitro 2D and 3D models (1R36AG070573-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10107973. Licensed CC0.

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