# Impact of Glycemic Control on Extracellular Vesicle-Mediated Angiogenesis in a Porcine Model of Chronic Myocardial Ischemia and Metabolic Syndrome

> **NIH NIH F32** · RHODE ISLAND HOSPITAL · 2021 · $73,062

## Abstract

Therapeutic options for end-stage, diffuse coronary artery disease (CAD), an important complication of
diabetes,1,2 remain limited. Regenerative therapies, including extracellular vesicles (EV), are promising
therapeutic options for diabetic patients with severe CAD who have failed other interventions. While animal-
based studies of cell therapy have been promising, clinical trials have failed to demonstrate similar efficacy in
CAD.5–7 This discrepancy may be due to altered signaling in the setting of metabolic syndrome (MS). The long
term goal of the applicant in pursuing this research fellowship is to develop a strong foundation and core skill
set in academic cardiothoracic research, with which he can launch a career as a cardiac surgeon scientist after
completing surgical clinical training. The overall objective of this project is to elucidate the molecular
mechanisms involved in EV-induced coronary collateral development in ischemic myocardium in a clinically
relevant porcine model of MS, specifically identifying the role of glycemic control in augmenting EV-induced
angiogenesis. The central hypothesis is that glycemic control will reduce reactive oxygen species (ROS), alter
AMP:ATP ratio, and increase VEGF-induced PI3K-Akt signaling, allowing for augmented EV-mediated
angiogenesis. The central hypothesis will be tested by pursuing two specific aims: 1) Identify the effects of
glycemic control on key signaling pathways involved in coronary angiogenesis and collateralization response of
ischemic myocardium to human bone marrow mesenchymal stem cell (HBMSC) derived EVs in a porcine model
of MS; 2) Identify the effects of hypoxia-modified HBMSC-derived EVs containing increased levels of
VEGF/HGF, glucose transporter SLC2A14, and Akt, on coronary angiogenesis and myocardial perfusion in
chronically ischemic myocardium in a porcine model of MS, with and without glycemic control. For both aims, a
porcine model of diet-induced MS and chronic myocardial ischemia using left circumflex ameroid constriction will
be used. Swine with MS and chronic myocardial ischemia with and without glycemic control using metformin will
be injected (intracardiac) with HBMSC-EV vs hypoxia-modified HBMSC-EV vs placebo. Analysis will be
performed on molecular expression of proteins involved in angiogenesis signaling, vessel density, myocardial
perfusion, and cardiac function. The research proposed in this application is innovative because it investigates
the use of HBMSC-EV to treat chronically ischemic myocardium in a clinically relevant large animal model of
metabolic syndrome, which more accurately reflects the complex pathophysiology and co-morbidities in human
patients. The proposed research is significant because it is expected to identify clinically relevant therapeutic
strategies that can enhance the angiogenic response of chronically ischemic myocardium to HBMSC-EV.
Ultimately, such knowledge may contribute to the development of innovative therapies for patients w...

## Key facts

- **NIH application ID:** 10314127
- **Project number:** 1F32HL160063-01
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** Sharif A. Sabe
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $73,062
- **Award type:** 1
- **Project period:** 2021-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314127

## Citation

> US National Institutes of Health, RePORTER application 10314127, Impact of Glycemic Control on Extracellular Vesicle-Mediated Angiogenesis in a Porcine Model of Chronic Myocardial Ischemia and Metabolic Syndrome (1F32HL160063-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10314127. Licensed CC0.

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