# OPA1 an Estrogen-Mediated Modulator of Platelet Hyperactivation

> **NIH NIH R33** · UNIVERSITY OF IOWA · 2020 · $724,311

## Abstract

Strong epidemiological evidence links pre-menopausal estrogen exposure to increased risk of venous
thrombosis in women, particularly during pregnancy, in the immediate postpartum period, and in women taking
estrogen-containing oral contraceptives (OCP). This proposal addresses a significant knowledge gap linking
estrogens with platelet activation. Studies in the past have focused on how estrogens alter the hemostatic and
fibrinolytic system. This proposal, which focuses on platelets, represents a productive collaboration between
the Universities of Iowa and Utah. Our preliminary studies in the Framingham cohort and in pregnant humans,
reveal increased platelet OPA1 levels in females, that predict risk of coronary artery disease, or correlate with
increased platelet activation in the third trimester of pregnancy. In platelet-deficient OPA1 knockout (KO) mice
we discovered that female OPA1KO mice were protected from thrombosis compared to males. The
thrombosis phenotype was reversed after oophorectomy. Based on these preliminary findings, we hypothesize
that OPA1 and regulators of OPA1 activity, OMA1 and YMEL1, modulate platelet activation in an
estrogen-dependent manner and OPA1 levels in platelets predict estrogen modulated platelet
activation. To address this hypothesis in the R61 phase, Aim 1 will determine the molecular mechanisms for
estrogen-mediated and OPA-1-dependent modulation of platelet activation using mice with platelet specific
OPA1 deletion and will generate OMA1 and YMEL1 platelet specific KO mice, with increased OPA1 activity.
Aim 2 will determine platelet OPA1, OMA1, and YMEL1 expression and correlate expression levels to platelet
activation in the setting of pregnancy and OCP use. We will also develop a human iPSC model system to
generate MKs to determine if estrogen directly regulates the expression of these genes. The R33 phase will
dissect the molecular mechanisms linking increased OPA1 with platelet activation in females. Aim 1 will
perform detailed physiological and molecular phenotyping of murine platelets isolated from OMA1 and YMEL1
KO and OPA overexpressing transgenic mice. In addition, we will examine the mechanisms linking increased
OPA1 activity, mitochondrial energetics and platelet activation. Aim 2 will complement animal studies by
examining changes in mitochondrial function and signaling in platelets from pregnant women and women on
OCPs. We will genetically ablate OMA1 and YMEL1 from iPSC-derived MKs to directly test if estrogen
modulates MK and platelet function in an OPA1 dependent manner. By integrating in vivo and in vitro studies
in humans and mouse models, our approach is translational, innovative and highly responsive to the RFA.
These studies will determine for the first time whether increased estrogen exposure in pregnancy and OCP use
reprogram MKs and developing platelets to increase thrombotic complications and identify novel mechanisms
for this increased risk. The impact of these studies, is that th...

## Key facts

- **NIH application ID:** 10026343
- **Project number:** 4R33HL141783-03
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** E Dale Abel
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $724,311
- **Award type:** 4N
- **Project period:** 2018-04-10 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026343

## Citation

> US National Institutes of Health, RePORTER application 10026343, OPA1 an Estrogen-Mediated Modulator of Platelet Hyperactivation (4R33HL141783-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10026343. Licensed CC0.

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