# Role of cytoglobin in promoting smooth muscle cell survival during maladaptive vascular remodeling

> **NIH NIH R01** · ALBANY MEDICAL COLLEGE · 2020 · $406,979

## Abstract

Our knowledge of mechanisms regulating vascular remodeling in atherosclerotic and non-
atherosclerotic vasculopathies is still inadequate. This represents an important rate-limiting step to
improve or design new therapeutic interventions that may prove beneficial during atherogenesis or in
advanced atherosclerotic lesions. In the cardiovascular system, globins including hemoglobin and
myoglobin are thought exclusively to transport and store molecular oxygen and regulate nitric oxide
bioavailability. However, recent evidence suggests that this model is not complete and mammalian
globins such as cytoglobin (CYGB) might have important functions in vascular remodeling that are
independent of oxygen storage and transport. We discovered that CYGB is abundantly expressed in
medial smooth muscle cells of rodent and human vessels. We have obtained strong preliminary results
showing that CYGB inhibits apoptosis during vascular injury in vivo and in vitro and we have generated
a floxed mouse line allowing for tissue specific deletion of CYGB. The goal of this proposal is to test
the general hypothesis that smooth muscle CYGB combines novel anti-apoptotic and nitric oxide
consuming functions that have favorable effects in inhibiting atherosclerotic plaque pathogenesis. In
Aim 1, we will test the hypothesis that smooth muscle specific conditional knockdown of CYGB will
increase smooth muscle cell apoptosis, with a detrimental loss of smooth muscle cells, and a decrease
in indices of plaque stability. We will use novel genetically encoded cell lineage tracing approaches in a
mouse model of atherosclerosis combined with targeted conditional deletion of smooth muscle CYGB.
In Aim 2, we will establish the contribution of nitric oxide signaling to the function of CYGB in the
vasculature and in advanced atherosclerotic plaques through functional and metabolomics
characterization combined with nitric oxide synthase (NOS) and CYGB genetic deletion. In Aim 3, we
will determine the mechanism of action of CYGB in apoptosis. To this end, we will establish the role of
CYGB in regulating the downstream effector of apoptosis caspase-3 through redox- and gene-
regulated inhibition of its activation. Finally, we will test the hypothesis that CYGB serves as an NO and
O2 sensor to regulate downstream signals. Overall, this work will be guided through studies of human
atherosclerotic plaque samples derived from asymptomatic and symptomatic patients. The results
derived from the proposed experiments will challenge the current dogma related to mammalian globin
functions as simply oxygen transport and nitric oxide handling systems. Ultimately, we hope to
delineate novel pro-survival pathways in the vasculature that could be manipulated to mitigate
inappropriate vascular remodeling through combined regulation of apoptosis and nitric oxide bio-
availability.

## Key facts

- **NIH application ID:** 9996772
- **Project number:** 5R01HL142807-02
- **Recipient organization:** ALBANY MEDICAL COLLEGE
- **Principal Investigator:** DAVID JOURD'HEUIL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $406,979
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996772

## Citation

> US National Institutes of Health, RePORTER application 9996772, Role of cytoglobin in promoting smooth muscle cell survival during maladaptive vascular remodeling (5R01HL142807-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9996772. Licensed CC0.

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