# Coronary microvascular rarefaction in diabetic/obese heart

> **NIH NIH R01** · UNIVERSITY OF MISSISSIPPI MED CTR · 2020 · $387,500

## Abstract

Summary: Microvascular rarefaction with reduced coronary flow reserve (CFR) has been shown
to contribute to diastolic dysfunction. Although a significant coronary microvascular rarefaction
occurs in type II diabetes/obesity, surprisingly, little is known about capillary rarefaction in diastolic
dysfunction. In the last grant cycle, we have showed that obesity/diabetes disrupts
angiopoietins/Tie-2 system in favor Ang-2, thus leading to microvascular phenotypic alterations
and capillary rarefaction with a reduction of CFR. The microvascular phenotypic
alterations/rarefaction and reduced CFR may render cardiomyocyte vulnerable to hypoxia, thus
leading to a diastolic dysfunction in diabetes/obesity. However, the molecular mechanisms that
lead to coronary microvascular phenotypic changes and capillary rarefaction in diabetes/obesity is
not clearly defined. This renewal proposal will specific investigate Sirtuin 3 (Sirt3), a metabolic
sensor, on EC glycolytic metabolism and capillary rarefaction. Aim 1: To define the mechanism(s)
by which ablation of endothelial Sirt3 leads to coronary microvascular dysfunction with a focus on
impairment of endothelial glycolytic metabolism. First, we will determine whether improvement of
glycolysis increases angiogenesis and mitochondrial function, and reduces ROS formation by
overexpression of HIF-2α in Sirt3 deficient EC in vitro. Further, we will determine whether
endothelial specific overexpression of HIF-2α upregulates PFKFB3 expression, increases
capillary density, restores CFR, and improves diastolic function in Sirt3ECKO mice and Sirt3ECKO-
DIO mice. Aim 2: To test the hypothesis that disruption of endothelial Sirt3-PFKFB3 signaling
pathway promotes microvascular rarefaction in diabetes. In vitro, we will determine whether
overexpression of PFKFB3 rescues impaired glycolysis, thus leading to increase in the expression
of angiogenic growth factors, reducing ROS formation and inflammation in Sirt3KO-EC. We also
determine whether specific overexpression of PFKFB3 in EC reduces ROS formation, attenuates
EC inflammation and prevents capillary rarefaction, and restores CFR and diastolic function in
Sirt3ECKO-DIO mice and diabetic db/db mice. Aim 3: To test the hypothesis that ablation of
endothelial Sirt3 promotes capillary rarefaction by a mechanism involving upregulation of Ang-2
and loss of pericytes in diabetes. We will determine whether blockade of Ang-2 rescues impaired
EC/pericyte coverage and attenuates coronary microvascular rarefaction in Sirt3ECKO and
Sirt3ECKO-DIO mice. Using Notch3KO/db/db mouse as a model of loss of pericytes, we will further
determine whether inhibition of Ang-2 attenuates loss of cardiac pericytes and coronary
microvascular rarefaction, improves CFR and diastolic function in diabetes.

## Key facts

- **NIH application ID:** 9882521
- **Project number:** 5R01HL102042-08
- **Recipient organization:** UNIVERSITY OF MISSISSIPPI MED CTR
- **Principal Investigator:** JIAN-XIONG CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,500
- **Award type:** 5
- **Project period:** 2010-07-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9882521

## Citation

> US National Institutes of Health, RePORTER application 9882521, Coronary microvascular rarefaction in diabetic/obese heart (5R01HL102042-08). Retrieved via AI Analytics 2026-06-23 from https://api.ai-analytics.org/grant/nih/9882521. Licensed CC0.

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