# The Role of the Cardiomyocyte HIF pathway and FOG2 in Coronary Microvascular Disease

> **NIH NIH K08** · UNIVERSITY OF PENNSYLVANIA · 2020 · $169,767

## Abstract

PROJECT SUMMARY
Coronary microvascular disease (CMVD), or disease of the coronary pre-arterioles, arterioles, and capillaries,
has become an increasingly well-recognized cardiac pathology, which carries a high burden of morbidity,
healthcare costs, and increased mortality. CMVD exists in isolation and also exacerbates other cardiac disease
such as coronary artery disease (CAD) and cardiomyopathies. In addition, the pathophysiology of CMVD also
has implications for heart failure with preserved ejection fraction (HFpEF) and coronary collateral formation.
The Hypoxia-Inducible Factor 1a (HIF) pathway is activated in response to hypoxia and has been studied in
the context of coronary microvasculature and cardiac perfusion. Signaling through the HIF pathway promotes
angiogenesis and may improve microvascular structure, however, the HIF pathway is known to have
deleterious metabolic effects on cardiomyocytes. Uncoupling the beneficial angiogenic and deleterious
metabolic effects of the HIF pathways would therefore be highly beneficial. Evidence that FOG2, a
transcriptional co-activator of GATA4, is a key regulator of coronary development and the maintenance of
coronary microvasculature into adulthood, have led to the novel hypothesis that FOG2 is a critical regulator
in the HIF pathway and that FOG2 can mediate HIF-induced coronary angiogenesis without deleterious
effects on cardiac metabolism. I have developed a translational framework consisting of 1) a mouse model
of CMVD and 2) functional imaging of the mouse coronary microvasculature to help investigate this hypothesis.
Three interrelated Specific Aims will address the hypothesis: 1) Characterize HIF-induced angiogenesis and
metabolic changes in cardiomyocytes and determine whether FOG2 mediates HIF induction of angiogenic and
metabolic pathways in cardiomyocyte cell culture; 2) Delineate the role of HIF and FOG2 pathways in CMVD
and determine whether FOG2 mediates HIF induction of coronary angiogenesis without affecting cardiac
metabolism in mice; and 3) Define the role of the HIF and FOG2 pathways in CMVD in humans. The
experiments in this innovative proposal will also have direct application toward the development of novel
therapies for CMVD. In addition, the research proposal is supported in an integrated manner through
exceptional mentorship, a research advisory committee filled with relevant expertise, and unequivocal
divisional and institutional commitment. Finally, this K08 award will serve as a basis for the achievement of my
ultimate career goal to become an independent physician-scientist at a major academic medical center.

## Key facts

- **NIH application ID:** 9897548
- **Project number:** 5K08HL136890-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Marie A Guerraty
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $169,767
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897548

## Citation

> US National Institutes of Health, RePORTER application 9897548, The Role of the Cardiomyocyte HIF pathway and FOG2 in Coronary Microvascular Disease (5K08HL136890-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897548. Licensed CC0.

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