# Estrogen as a Regulator of the Sphingolipid Balance in the Human Microcirculation

> **NIH NIH K08** · MEDICAL COLLEGE OF WISCONSIN · 2022 · $105,854

## Abstract

ABSTRACT
Microvascular endothelial dysfunction predicts future major adverse cardiac events (MACE). Sphingolipids,
biologically active lipids, are potent regulators of endothelial function and also prevent or promote the
development of heart disease. The studies proposed are an expansion of the current project which uses a unique
and translational approach to examine the effects of sphingolipid metabolism on the mediator of flow-induced
vasodilation (FID) within the human microvasculature. Arterioles exposed to ceramide, a sphingolipid that when
elevated in plasma is an independent risk factor for MACE, dilate in response to flow by generating H2O2, a pro-
inflammatory and pro- atherosclerotic mediator as opposed to nitric oxide (NO), the anti-inflammatory, anti-
atherosclerotic mediator utilized by healthy adults. On the contrary, sphingosine-1-phosphate (S1P), also within
the sphingolipid family and a metabolite of ceramide, restores NO-dependent FID in arterioles from patients with
coronary artery disease (CAD). Estrogen is a known regulator of the sphingolipid balance and interestingly can
stimulate production of S1P or ceramide. Estrogen-induced S1P formation may explain its protective role in pre-
menopausal women, whereas estrogen supplementation may tip the balance towards ceramide in microvessels
from older women thus increasing cardiovascular disease risk. The two aims proposed extend the current work
by investigating the effect of estrogen (physiological and elevated) on the mediator of FID in human microvessels
from both young and older females. Preliminary data suggest that sex-specific differences are also observed
with estrogen and therefore may have implications for the trans-female population. The S1P:ceramide ratio in
response to both physiological and elevated levels of estrogen treatment will be measured in sex-specific
endothelial cells. These studies are in the scope of the funded parent grant and will offer valuable insight into
how loss of estrogen during the transition to menopause, as well as how elevated amounts of estrogen (e.g. oral
contraceptives, hormone therapy), increases future cardiovascular disease risk. Data generated from this
proposal will add critical mechanistic insight into the positive and negative microvascular effects of estrogen in
both cis-gender females throughout the lifespan as well as the trans-female population.

## Key facts

- **NIH application ID:** 10556913
- **Project number:** 3K08HL141562-04S1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Julie K Freed
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $105,854
- **Award type:** 3
- **Project period:** 2022-09-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10556913

## Citation

> US National Institutes of Health, RePORTER application 10556913, Estrogen as a Regulator of the Sphingolipid Balance in the Human Microcirculation (3K08HL141562-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10556913. Licensed CC0.

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