# Mechanistic Analysis of Aortic Growth and Remodeling due to Hyperglycemia and Recovery

> **NIH NIH F31** · UNIVERSITY OF MINNESOTA · 2024 · $42,574

## Abstract

PROJECT SUMMARY
 Diabetes is a heterogeneous disease characterized by chronic poor glycemic control, resulting in
pathological changes in tissues throughout the body. Chronic hyperglycemia causes the cardiovascular system
to undergo growth and remodeling (G&R) that is captured hypertension and increased arterial stiffness, both
significant risk factors for cardiovascular disease. Diabetes results in both cellular and matrix changes in arterial
health, and then each of these components further drive the pathological G&R by responding to the direct effects
of the disease. Fortunately, there exist medical and lifestyle interventions to help mitigate the diabetic disease
state and restore glycemic control. Large elastic arteries like the aorta serve as capacitors to absorb changes in
blood volume due to pulsatile pumping and protect the more fragile downstream microvasculature. Overall health
and stiffness of these large vessels is captured in the clinic via pulse wave velocity which is elevated in diabetic
patients, and there is evidence that the pulse wave velocity decreases back towards baseline following
restoration of glycemic control. The overarching objective of this project is to determine how hyperglycemia
affects aortic biomechanics and mechanobiology and whether restoration of normoglycemia is sufficient to
reverse these changes. To establish how arterial biomechanics are affected by hyperglycemia, I first employed
a diabetic mouse model to ascertain changes in active and passive wall mechanics, and these preliminary results
demonstrate that chronic hyperglycemia results in stiffer and hypercontractile murine aortas. The central
hypothesis of this proposal is that chronic hyperglycemia results in cellular and matrix aortic G&R, and glycemic
recovery results in reversal of the cellular, but not matrix, phenotype, leading to partial rescue of aortic health.
To test this hypothesis, I will utilize an inducible mouse model of chronic hyperglycemia that can subsequently
be rescued by administration of Phloridzin. Experiments proposed in Aim 1 will determine the in vivo and ex vivo
biomechanical changes in aortic health due to hyperglycemia and following treatment. Aim 2 will then explore
how the tissue-scale mechanical changes arise by investigating how the matrix composition and cellular
phenotype are affected by the disease and treatment. The experimental work of the first two Aims will be coupled
with a multiscale, bio-chemo-mechanical computational model of aortic G&R in Aim 3. The computational model
will provide mechanistic insight into the roles of cells and matrix in disease progression and possible regression,
resolving information that is inextricable experimentally. Collectively, these data will elucidate aortic G&R due to
chronic hyperglycemia, whether these changes can be reversed by restoration of glycemic control, and the
mechanisms behind these processes. This proposed work will have broad implications in the conceptual
understa...

## Key facts

- **NIH application ID:** 10900173
- **Project number:** 1F31HL173986-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Shannon M Flanary
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $42,574
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900173

## Citation

> US National Institutes of Health, RePORTER application 10900173, Mechanistic Analysis of Aortic Growth and Remodeling due to Hyperglycemia and Recovery (1F31HL173986-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10900173. Licensed CC0.

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