# Impact of sex and sex hormones on mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA-IRVINE · 2022 · $94,905

## Abstract

PROJECT ABSTRACT
The role of sex in cardiovascular disease (CVD) remains a critically understudied area in determining the
etiology, pathology, and effective treatments. Whereas men experience a gradual increase in CVD risk over the
lifespan, premenopausal women are protected from CVD-related pathologies. However, post-menopause the
onset of CVD in women increases dramatically. Endothelial cell dysfunction may contribute to these sex and sex
hormone-dependent differences in CVD risk. Here we seek to investigate the impact of sex and sex hormone-
dependent differences in progression of the CVD disease pulmonary hypertension secondary to left heart failure
(PH-LHF).
Aim 1: Investigate the role of sex and sex hormones in pulmonary endothelial cell mechanotransduction
and disease progression. First, we will test the hypothesis that female sex alters endothelial cell signaling in
response to mechanical shear stress. Human male and female pulmonary artery, vein, and microvascular
endothelial cells will be exposed to physiologic, high, and low levels of shear stress (σ) to measure the effect of
sex independent of sex hormones. Second, to investigate the role of sex coupled with female sex hormones,
both male and female cells will be dosed with sex hormones at physiologic or pathologic σ. These in vitro results
will be confirmed as drivers of collagen over-production and chronic vasoconstriction in vivo using the established
mouse model of PH-LHF.
Aim 2: Determine the role of sex and sex hormones in the progression of PH-LHF with a coupled
pulmonary hemodynamics and endothelial cell kinetics model of PH-LHF. Informed by the existing
literature, we will develop a chemical kinetics model of the endothelial response to altered σ, sex, and sex
hormones. Using idealized human structural and hemodynamic data we will develop a computational model of
the pulmonary vasculature integrated with the chemical kinetics equations for key signaling factors. Parameter
values and dependencies will be validated against the in vitro data collected in Aim 1. To confirm predictive
capability, the model will be calibrated to the in vivo mouse model of PH-LHF and used to estimated pulmonary
artery and vein remodeling.

## Key facts

- **NIH application ID:** 10598399
- **Project number:** 3R01HL147590-04S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA-IRVINE
- **Principal Investigator:** Naomi C Chesler
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $94,905
- **Award type:** 3
- **Project period:** 2020-06-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10598399

## Citation

> US National Institutes of Health, RePORTER application 10598399, Impact of sex and sex hormones on mechanobiological mechanisms of pulmonary hypertension secondary to left heart failure (3R01HL147590-04S1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10598399. Licensed CC0.

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