# PDE10A Regulation and Function in Cardiovascular Disease

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2020 · $523,209

## Abstract

SUMMARY- Intimal hyperplasia characterized by abnormal accumulation of smooth muscle cell (SMC)-like
cells and inflammatory cells is a hallmark of vascular occlusive disorders such as post angioplasty restenosis,
vein graft atherosclerosis, and allograft vasculopathy. The current therapies with drug-eluting stents to inhibit
SMC proliferation and induce SMC death still have problems due to limited endothelial cell regrowth and
increased risk of thrombosis. Moreover, drug-eluting stents effective for focal lesions are not appropriate for
diffuse atherosclerotic disease. Thus, there is high demand to develop novel therapeutic strategies. Our
unbiased genome-wide genetic polymorphism association study in mice has identified cyclic nucleotide
phosphodiesterase 10A (PDE10A, catalyzing cyclic nucleotide hydrolysis) as a potential candidate gene
contributing to injury-induced intimal hyperplasia. Indeed, PDE10A expression is markedly elevated in the
intimal SMC-like cells and macrophages in mouse models of vascular injury and in human atherosclerotic
lesions. Our preliminary data with PDE10A knockout mice and PDE10 inhibitor suggest that PDE10A is
important in pathological vascular remodeling in vivo. In cultured SMCs, PDE10A depletion or inhibition
increases myocardin protein (a master driver of SMC contractile phenotype) and expression of several SMC
contractile marker genes. In macrophages, we found that PDE10A is important for NLRP3 inflammasome
expression and activation. PDE10A expression is up-regulated by growth factors and inflammatory cytokines.
Bioinformatic analysis identified a highly conserved intronic putative transcriptional regulatory sequence at the
single-nucleotide polymorphism (SNP) site identified by our mouse genetic association study, and it may be
responsible for regulating PDE10A gene expression during phenotype switching and stimulation of
inflammation. Thus, we hypothesize that increased PDE10A expression, by inhibiting cAMP signaling,
promotes synthetic SMC phenotype transition and macrophage inflammasome expression/activation; and thus
stimulates intimal hyperplasia. The overall objective of this proposal is to investigate the mechanisms that
regulate expression of PDE10A, and PDE10A's specific role in the processes responsible for intimal
hyperplasia. To achieve our goals, two Specific Aims are proposed: (1) Determine the role of PDE10A in
intimal formation and vascular remodeling after injury using both genetic and pharmacological approaches. (2)
Define the mechanisms for PDE10A regulation of vascular pathology: regulation of PDE10A expression,
transition of SMC phenotype, and stimulation of vascular inflammation. PDE10A is well known in psychosis;
and PDE10A inhibitor has been developed for clinical trials to treat schizophrenia. However, PDE10A
regulation and function in cardiovascular system remains largely unknown. Our studies should yield novel
therapeutic strategies to limit pathologic intimal hyperplasia given PDE10...

## Key facts

- **NIH application ID:** 9888405
- **Project number:** 5R01HL134910-04
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Bradford C Berk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $523,209
- **Award type:** 5
- **Project period:** 2017-03-10 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9888405

## Citation

> US National Institutes of Health, RePORTER application 9888405, PDE10A Regulation and Function in Cardiovascular Disease (5R01HL134910-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9888405. Licensed CC0.

---

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