# Sympathetic-Vascular Dysfunction in Obesity-Related Hypertension

> **NIH NIH R01** · UNIVERSITY OF KANSAS MEDICAL CENTER · 2021 · $460,624

## Abstract

PROJECT SUMMARY
 Obesity is highly prevalent in the U.S. and has significant consequences for mortality and quality of life.
Obesity is the primary gateway to additional cardiovascular disease (CVD) risk factors such as increased insulin
resistance, dyslipidemia, and hypertension. Prospective studies have estimated that nearly 75% of cases of
hypertension can be attributed to obesity. Hallmarks of obesity-related hypertension are oxidative stress, chronic
inflammation, and vascular dysfunction. However, our understanding of the precise mechanisms underlying the
development of hypertension in obesity and insulin resistance remains incomplete. We hypothesize that
hyperglycemia and hyperlipidemia augment vascular sensitivity to single bursts of sympathetic nerve activity
(SNA) via oxidative stress to heighten blood pressure variability in obesity and insulin resistance. Using a double-
blinded, placebo-controlled, randomized approach, we will determine the extent to which sympathetic-vascular
transduction is elevated by hyperglycemia and hyperlipidemia and resultant oxidative stress and the extent to
which suppression of oxidative stress via ascorbic acid attenuates the exaggerated increase in vascular
sensitivity to single bursts of SNA. Given our innovative approach, these studies provide direct insight into the
ability of single bursts of SNA to dynamically regulate vascular tone and blood pressure. We will also test the
novel hypothesis that sympathetic blockade mitigates the pro-inflammatory phenotype of obesity. Obesity is also
characterized by chronic inflammation, which is mediated in part by the sympathetic nervous system. Expression
of pro-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) can be regulated by norepinephrine.
The urgency to mitigate inflammation in obesity has recently been accelerated by the increased risk of poor
outcomes following infection by SARS-CoV-2. Indeed, recent data show that circulating concentrations of pro-
inflammatory cytokines such as interleukin 6 (IL-6) are positively correlated with poor outcomes in patients with
SARS-CoV-2. We propose sympathetic blockade as a novel approach to mitigating the pro-inflammatory
phenotype of obesity and hypertension. To demonstrate feasibility of our hypothesis, we have performed pilot
studies using a randomized, double-blinded, parallel study design in a small group of overweight/obese adults
using 4 weeks of oral clonidine to reduce central sympathetic outflow and observed significant reductions in
MSNA and circulating TNF-α but no change in MSNA and circulating TNF-α following 4 weeks of placebo or
hydrochlorothiazide (HCTZ) as a BP-lowering control condition. We plan to extend these preliminary data in our
outlined studies to achieve sufficient power to observe signficant and clinically meaningful group differences in
circulating and endothelial cell pro-inflammatory cytokines. The long-term goal of our research is to identify
unique mechanisms that ca...

## Key facts

- **NIH application ID:** 10280855
- **Project number:** 1R01HL159370-01
- **Recipient organization:** UNIVERSITY OF KANSAS MEDICAL CENTER
- **Principal Investigator:** SETH WILLIAM HOLWERDA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $460,624
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10280855

## Citation

> US National Institutes of Health, RePORTER application 10280855, Sympathetic-Vascular Dysfunction in Obesity-Related Hypertension (1R01HL159370-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10280855. Licensed CC0.

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