# Arterial Stiffening and Mechanics in Hutchinson-Gilford Progeria Syndrome

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2020 · $28,470

## Abstract

Project Summary:
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disease caused by a mutation in the
nuclear structural protein Lamin A. HGPS children exhibit similar phenotypes as aged individuals, including a
stiffening of the large elastic arteries. Increased arterial stiffness is correlated with increased risk of
cardiovascular disease, and HGPS children die in their early teens due to heart attack and stroke, likely induced
by large atherosclerotic lesions. However, the mechanisms initiating and promoting arterial stiffness in HGPS
are not well characterized. Vascular smooth muscle cells (VSMCs) reside in the media layer of the arteries and
exist along a phenotypic spectrum from contractile (differentiated) to synthetic, matrix producing cells
(dedifferentiated). Arterial stiffening is characterized by increased extracellular matrix deposition by the VSMC
population, including enhanced deposition of collagen-I and crosslinking of collagens through Lysyl Oxidase
(LOX). The proposed study will seek to identify the contribution of VSMC differentiation state to arterial stiffening
in HGPS. Using a well-established HGPS mouse model, I will first compare differentiation state between Wild-
type and HGPS VSMCs. Then, I will assess the contribution of YAP signaling, a pathway shown to regulate both
VSMC differentiation state and collagen production, to arterial stiffening in HGPS. Finally, I will assess how
inhibition of collagen-I cross-linking by LOX contributes to arterial stiffening.
Hypothesis: I hypothesize that HGPS vascular smooth muscle cells exist in a more synthetic state and
produce higher levels of collagen-I and LOX, which contribute to increased arterial stiffness. I hypothesize that
a decrease in collagen-I deposition or cross-linking can alleviate arterial stiffness in HGPS.
Aim 1: Characterize the differentiation state of VSMCs in vivo and identify YAP signaling as a potential
mechanism for enhanced collagen-I production.
Aim 2: Characterize the contribution of collagen-I crosslinking by LOX to arterial stiffness in HGPS using
pharmacologic LOX inhibitor β-aminopropionitrile.

## Key facts

- **NIH application ID:** 9998006
- **Project number:** 5F31HL142160-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ryan von Kleeck
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $28,470
- **Award type:** 5
- **Project period:** 2018-09-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9998006

## Citation

> US National Institutes of Health, RePORTER application 9998006, Arterial Stiffening and Mechanics in Hutchinson-Gilford Progeria Syndrome (5F31HL142160-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9998006. Licensed CC0.

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