# Role of cyclic nucleotide signaling in aortic aneurysm

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2022 · $580,434

## Abstract

ABSTRACT- Aortic aneurysm (AA) is characterized by localized abnormal dilatation or bulging of aorta due to
weakened vessel wall. AA occurs in different sections of aorta, such as thoracic AA (TAA) and abdominal AA
(AAA). The rupture of aneurysm has high mortality and requires immediate surgical repair. Aortic smooth muscle
cells (SMCs), by regulating aortic contractility and elasticity, are critical for reducing aortic wall stress in response
to the pulsatile high-pressure blood flow from the heart. SMC loss and dysfunction can cause medial
degeneration and contribute to AA development. cAMP and cGMP, are important regulators of SMC contractile
function and vessel wall structural integrity. Cyclic nucleotide phosphodiesterases (PDEs), by catalyzing cAMP
and/or cGMP degradation, play crucial roles in specific modulation of cyclic nucleotide signaling and have been
proved to be promising drug targets in highly specific pharmacological interventions. Recently, a few sporadic
lines of clinical and experimental evidence have suggested that stimulating cAMP and cGMP signaling may have
different, even opposite, effects on AA and/or dissection. In this application, we will focus on two PDE1 family
isozymes and AAA. Previous studies from our lab and others have shown that among three PDE1 members (1A,
1B, and 1C), PDE1A and 1C are two major PDE1 isozymes expressed in contractile and/or synthetic SMCs.
PDE1A and 1C primarily hydrolyze cGMP and cAMP, respectively, in SMCs. We recently found that in the human
and mouse aortic tissues, PDE1C is highly induced in synthetic SMC-like cells of AAA compared to normal
controls. PDE1A is expressed in SMCs of both normal and AAA tissues. Interestingly, targeting PDE1A and 1C
likely have opposing effects in AAA: PDE1A deficiency aggravates while PDE1C deficiency attenuates
experimental AAA in mice. PDE1A regulates the contractility of contractile SMCs, and is important for synthetic
SMC survival. However, PDE1C induction promotes SMC phenotype switching, senescence, and death.
Interestingly, the protective effects from PDE1C inhibition overcome the detrimental effects from PDE1A
inhibition in SMCs. These mechanistic differences may be responsible for their functional differences in AAA.
Thus, we hypothesize that chronic PDE1C inactivation suppresses SMC phenotype switching, senescence,
death, and ECM degeneration (e.g. MMPs), thus attenuating experimentally induced mouse AAA. In contrast,
chronic PDE1A inactivation causes SMC contractile dysfunction and increases aortic wall stress, as well as
promotes synthetic SMC death and ECM degeneration, thus exacerbating experimentally induced AAA.
Inhibiting PDE1A/1C together produces a protective effect against AAA because the effect of PDE1C inhibition
overrides the effect of PDE1A inhibition. We will study the regulation, function and mechanism of PDE1A or 1C
in AAA and evaluate the pharmacological effects by targeting PDE1 in AAA. The translational significance of this
st...

## Key facts

- **NIH application ID:** 10538778
- **Project number:** 1R01HL162259-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Chen Yan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $580,434
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538778

## Citation

> US National Institutes of Health, RePORTER application 10538778, Role of cyclic nucleotide signaling in aortic aneurysm (1R01HL162259-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10538778. Licensed CC0.

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