# Physiological mechanisms governing soluble guanylyl cyclase redox regulation in resistance arteries

> **NIH NIH F32** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $52,715

## Abstract

PROJECT SUMMARY/ABSTRACT
Nitric oxide (NO) regulates blood pressure by binding reduced heme iron (Fe2+) in soluble guanylyl cyclase (sGC)
activating production of cyclic guanosine 3', 5'-monophosphate (cGMP) and relaxing vascular smooth muscle
cells (SMC). In cardiovascular diseases, increased oxidative stress can cause oxidation (Fe3+) or loss (apo-) of
the sGC heme impairing NO binding and causing vasoconstriction. A new class of therapeutic compounds,
termed sGC activators have been developed to target the oxidized heme sGC and, more robustly, heme-deficient
apo-sGC to restore cGMP production and induce vasodilation independent of NO or disease. However, these
sGC activators have failed Phase 2 clinical trials due in part to patients developing sustained, systemic
hypotension. Surprisingly, little is known about the impact of sGC activator use under physiological conditions,
representing a major gap in our knowledge of sGC function. Our preliminary vascular function studies have
uncovered that resistance arteries were log-orders more sensitive to sGC activator than conduit arteries in non-
stressed conditions. This suggests, for the first time, that resistance arteries may contain a previously
unrecognized physiological pool of oxidized heme and/or apo-sGC that can be activated independent of NO or
disease. We have previously shown in cultured SMC that cytochrome b5 reductase 3 (CYB5R3) regulates sGC
redox state by reducing oxidized heme sGC back to its NO-sensitive reduced state (Fe3+->Fe2+). Our preliminary
studies in transgenic CYB5R3 overexpression (CYB5R3 OE) mice show that resistance, but not conduit, arteries
had a diminished response to sGC activator induced vasodilation and blood pressure lowering. We also found
pre-treatment of resistance arteries with reactive oxygen species scavengers or anti-oxidant compounds reduced
resistance vessel vasodilation to sGC activator. Thus we hypothesize in physiological conditions, resistance
arteries have a pool of oxidized heme or apo-sGC and CYB5R3 and endogenous O2- and H2O2 can modulate
sensitivity to sGC activator treatment potentially through governing sGC redox state. This grant will focus on
non-stressed resistance arteries and 1) explore basal sGC redox state and if it is modulated by CYB5R3, and 2)
determine if CYB5R3, O2-, and/or H2O2 confer their sensitivity to sGC activator therapy. For Aim 1, we will assess
vasodilation and cGMP production in CYB5R3 OE, SMC-specific CYB5R3 knockout, and littermate control mice
in response to sodium nitroprusside (reduced heme sGC), sGC activator BAY 58-2667 (oxidized heme and apo-
sGC), and protoporphyrin IX (apo-sGC). In Aim 2, we will use a combination of pharmacological compounds and
mouse models to modulate levels of CYB5R3, and non-mitochondrial and mitochondrial sources of O2- and H2O2
to assess if this can impact resistance artery sensitivity to sGC activator induced vasodilation. Completion of
these aims will provide greater insight into physi...

## Key facts

- **NIH application ID:** 9990089
- **Project number:** 1F32HL152498-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Brittany Grace Durgin
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $52,715
- **Award type:** 1
- **Project period:** 2020-07-01 → 2021-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9990089

## Citation

> US National Institutes of Health, RePORTER application 9990089, Physiological mechanisms governing soluble guanylyl cyclase redox regulation in resistance arteries (1F32HL152498-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9990089. Licensed CC0.

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