# Arterial stiffening and SMC mechanobiology in Hutchinson-Guilford Progeria Syndrome

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $383,918

## Abstract

SUMMARY
Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disease of premature aging caused by an
autosomal dominant mutation in LMNA, the gene encoding laminA. The mutant protein, LmnAG608G has been
named "Progerin." Children with HGPS typically die in their teenage years as a consequence of CVD
(atherosclerosis, myocardial infarction and/or stroke). Remarkably, CVD and death occurs in the absence of
high cholesterol, but the arteries of HGPS patients are abnormally stiff, and arterial stiffness has been
identified as a cholesterol-independent risk factor for CVD. Moreover, we previously showed that in vivo
inhibition of arterial stiffening reduces atherosclerosis in apoE-null mice. Because Progerin is aberrantly
farnesylated, therapies for HGPS have focused farnesyltransferase inhibitors (FTIs), but those studies do not
directly address the cardiovascular pathology that is thought to trigger early death in HGPS.
We recently obtained the LMNAG609G mouse that corresponds to the LMNAG608G mutation in human HGPS and
show here that this mouse phenocopies the human disease in showing premature arterial stiffening.
Immunostaining of arterial sections and an ECM expression array have identified two lead candidates for this
premature arterial stiffening, and those will be studied here. We also found that HGPS arteries are deficient in
their response to vasoconstrictors, and our preliminary results link this contractility defect to a striking
uncoupling of two well established smooth muscle differentiation/CArG genes: expression of smooth muscle
myosin heavy chain (SM-MHC) is reduced in HGPS while smooth muscle actin (SMA) levels are relatively
normal. Importantly, we have been able to recapitulate this in vivo phenotype of uncoupled SM-MHC vs. SMA
expression in primary smooth muscle cells (SMCs) from WT and HGPS aortas. SM-MHC is among the most
important regulators of the high contractility state in differentiated SMCs. Thus, these findings, and related
traction force microscopy (TFM) experiments in Preliminary Studies, lead us to a new model for premature
arterial stiffening in HGPS: the expression of mutant LaminA (Progerin) leads to a preferential downregulation
of SM-MHC, and this locks HGPS SMCs into a novel intermediate tensional state in which they behave more
like a de-differentiated SMC, producing ECM proteins and ECM remodeling enzymes that lead to an
acceleration of arterial stiffening. Aim 1 will use age-matched WT and HGPS mice to test for causal
relationships between i) ECM remodeling events and premature arterial stiffening and ii) SM-MHC expression
and arterial ECM remodeling. Aim 2 will use isolated SMCs to identify molecular mechanisms and causal
relationships between HGPS, SM-MHC expression, cellular contractility, and ECM remodeling. It will also
establish molecular mechanisms by which expression of Progerin, and possibly WT LaminA, affects SM-MHC
gene expression. Aim 3 will test for similarities and differences between a...

## Key facts

- **NIH application ID:** 10368103
- **Project number:** 5R01AG062140-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Richard Assoian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $383,918
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10368103

## Citation

> US National Institutes of Health, RePORTER application 10368103, Arterial stiffening and SMC mechanobiology in Hutchinson-Guilford Progeria Syndrome (5R01AG062140-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10368103. Licensed CC0.

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