# Novel Regulatory Mechanisms in the Human Microcirculation

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $424,321

## Abstract

Project Abstract
The microvasculature plays a critical role in the development and consequences of a broad range of
cardiovascular diseases. The main assessment of microvascular function is via endothelium-dependent NO-
mediated dilation which is reduced as a precursor to coronary artery disease (CAD) and cardiomyopathy. In
human arterioles from subjects with CAD loss of NO-mediated flow-mediated dilation (FMD) is compensated by
hydrogen peroxide (H2O2) from endothelial mitochondria. Although both are dilators, NO and H2O2 have
opposing effects on vascular health, with NO promoting quiescence and H2O2 promoting vascular and
parenchymal inflammation leading to atherosclerosis. Understanding mechanisms responsible for this switch in
mediator may be key to minimizing tissue stress or injury from vascular paracrine redox toxicity.
 The goal of this study is to determine fundamental cellular pathways regulating this switch from NO to H2O2.
We propose that two systems, recently shown to be shear sensitive and fundamental to cell function are linked
as critical for FMD in human arterioles (HA). The first is autophagy which we propose is the controlling switch
that regulates shear-induced production of NO or H2O2. Blocking autophagic flux reduces NO and enhances
reactive oxygen species (ROS). The second pathway involves lipid phosphate phosphatase 3 (LPP3), which
responds to shear by inhibiting lysophosphatidic acid (LPA), lowering ROS and promoting NO. A single
nucleotide polymorphism of this gene, seen in 80% of the population is associated with heightened risk for CAD.
We propose that shear-induced activation of LPP3 is needed to maintain NO-mediated FMD in HA.
 Neither LPP3 nor autophagy has been linked to the mediator of FMD. We will study fresh human coronary
and adipose arterioles in human microvascular endothelial cells in vitro using stimulators and inhibitors of
autophagy and LPA to determine their role in FMD. The local tissue impact can be profound given the different
effect of NO vs. H2O2 on cardiovascular function. We will test the following hypotheses:
Hypothesis 1. Autophagy is critical in maintaining NO as the mediator of FMD in the human coronary
microcirculation. Reduced autophagy leads to a switch to H2O2 as the mediator of FMD.
Hypothesis 2. LPP3 is upregulated by microvascular endothelial shear resulting in LPA hydrolysis, attenuation
of endothelial ROS, with maintenance of NOS-dependent FMD. If LPP3 is mechanistically linked to
microvascular dysfunction, this could be an important target, either directly or through LPA, for reducing the
vascular inflammation in a large number of genetically CAD-susceptible individuals.

## Key facts

- **NIH application ID:** 9839414
- **Project number:** 5R01HL135901-04
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** David D. Gutterman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $424,321
- **Award type:** 5
- **Project period:** 2016-12-12 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839414

## Citation

> US National Institutes of Health, RePORTER application 9839414, Novel Regulatory Mechanisms in the Human Microcirculation (5R01HL135901-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9839414. Licensed CC0.

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