# Medial Arterial Calcification: Mechanisms and Therapy

> **NIH NIH R01** · CLEMSON UNIVERSITY · 2021 · $582,538

## Abstract

Monckeberg's arteriosclerosis is a form of vessel hardening in which calcium deposits are found in the medial
layer of elastic and muscular arteries, specifically on elastic fibers, leading to arterial stiffening and tearing. An
independent risk factor for cardiovascular diseases in diabetic and chronic kidney-disease patients, it
predisposes patients to cardiovascular mortality and lower extremity amputation. There are no treatments to
reverse calcification. Elastin protein has a half-life of >60 years with almost no turnover. During aging and disease
processes, elastic fibers degrade and are prone to calcification. We have developed unique nanoparticles that
can be targeted to degraded elastic lamina in vasculature while sparing healthy arteries. This project is focused
on removing mineral deposits by targeting chelating agent ethylene diamine tetra acetic acid (EDTA) to the
degraded and calcified elastin in arteries. Then, nanoparticles loaded with pentagalloyl glucose (PGG) will be
targeted to seal calcium-binding sites, inhibit enzymatic degradation, and restore lost elastin to improve vascular
elasticity. Our strong published data show that such targeted EDTA chelation therapy, based on albumin
nanoparticles, reverses experimentally created vascular calcification and avoids possible side effects of systemic
chelation therapy. We would like to take this approach forward in a clinically relevant animal model of chronic
kidney failure caused by adenine and high phosphorus diet.
In Specific Aim 1, we will test the hypothesis that reversal of elastin-specific vascular calcification is possible
when targeted nanoparticles deliver a chelating agent, EDTA, to the site of vascular calcification in a rat model
of adenine-induced uremia that causes vascular calcification. We will also determine whether calcification returns
after termination of EDTA therapy by monitoring animals for extended periods and whether such therapy has
any adverse effect on bone density and organ health. In Specific Aim 2, we will test the hypothesis that dual
therapy of targeted NPs carrying EDTA (to remove mineralization) followed NPs carrying PGG (to block calcium
binding sites) will prevent return of vascular calcification and improve vascular function irrespective of CKD
disease in a rat model of adenine-induced uremia. Such PGG therapy will also prevent further enzymatic
degradation of elastin and reverse chondro/osteogenic phenotypic change of vascular smooth muscle cells. In
Specific Aim 3, using genetically altered mice, we will test the hypothesis that permanent reversal of calcification
will lead to vascular homeostasis through reversing transdifferentiation of VSMC-osteoblast-like cell transition or
by repopulation of media with new VSMCs from either pericytes, endothelial to mesenchymal transition
(EndoMT), or hematopoietic stem cell (HSC) migration.
With successful completion of these studies, we will, for the first time, have developed a targeted therapy
approa...

## Key facts

- **NIH application ID:** 10070646
- **Project number:** 5R01HL145064-03
- **Recipient organization:** CLEMSON UNIVERSITY
- **Principal Investigator:** Naren R Vyavahare
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $582,538
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10070646

## Citation

> US National Institutes of Health, RePORTER application 10070646, Medial Arterial Calcification: Mechanisms and Therapy (5R01HL145064-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10070646. Licensed CC0.

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