# Elucidating the role of cardiac myofibroblasts on matrix and vasculature remodeling

> **NIH NIH F31** · UNIVERSITY OF WASHINGTON · 2020 · $40,714

## Abstract

In every form of heart disease, the secretion of extracellular matrix (ECM) by activated
fibroblasts, or myofibroblasts, results in cardiac fibrosis. Fibrosis impedes compliance and
pumping function, ultimately leading to heart failure due to left ventricular dilation and loss of
mechanical function. Little is known about endothelial cell and vessel adaptations to the
environment or how local mechanics and chemistry impact vessel structure and flow in vivo.
Combinatorial fibroblast and ECM mechanical and chemical crosstalk with endothelial cells are
unknown. Moreover, in vitro models aiming to assess vascular adaptations to an extracellular
environment lack physiologically relevant ECMs and instead provide exogenous ECM
components to optimize control of variables. A system for in vivo, cell-specific phenotypic
manipulation will allow for controlled perturbations at an organ level while maintaining relevant,
native ECM remodeling over time. Thus, I propose to examine transgenic mice with cardiac
fibroblast-specific overexpression of a constitutively active mitogen-activated protein kinase
kinase 6 (MKK6) to study vascular remodeling with respect to the fibroblasts and the ECM they
secrete. These mice were previously shown to develop interstitial and perivascular fibrosis after
16-20 weeks of the MKK6 gene activation without an injury stimulus, serving as an effective
model of the interstitial fibrosis preserved across the results of aging, hypertension, aortic
stenosis, and other diseases of the heart. Importantly, the remodeling seen in these diseases
does not involve a massive loss of cardiomyocytes, as in a myocardial infarction, but rather a
conserved fibroblast phenotypic change, an altered extracellular space, and/or restricted
vascular flow over time. Similarly, manipulation of the MKK6 pathway allows for overexpression
or knockdown of cardiac fibroblast activation, corresponding to increased ECM or the inability to
secrete ECM as a response to a stimulus, respectively. First, I propose to study the
biochemical, structural, and mechanical properties of the ECM as well as the macro- and
microvascular responses to activated, quiescent, and control cardiac fibroblast phenotypes in
vivo. Second, three-dimensional vessel-like structures with controlled fibroblasts and ECMs will
be engineered as in vitro platforms to define the molecular regulators of vascular remodeling
induced by microenvironmental cues. The effects of combined signaling will be resolved by
global characterization along with a reductionist method. The goal of this work is to inform heart
therapies by providing targets for steering cardiac vascular remodeling.

## Key facts

- **NIH application ID:** 9909793
- **Project number:** 1F31HL151017-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** EMILY OLSZEWSKI
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,714
- **Award type:** 1
- **Project period:** 2020-05-16 → 2023-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9909793

## Citation

> US National Institutes of Health, RePORTER application 9909793, Elucidating the role of cardiac myofibroblasts on matrix and vasculature remodeling (1F31HL151017-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9909793. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*