Role of cAMP-phosphodiesterase 1C signaling in regulating growth factor receptor stability, vascular smooth muscle cell growth, migration, and neointimal hyperplasia.
Circ Res
; 116(7): 1120-32, 2015 Mar 27.
Article
in En
| MEDLINE
| ID: mdl-25608528
ABSTRACT
RATIONALE Neointimal hyperplasia characterized by abnormal accumulation of vascular smooth muscle cells (SMCs) is a hallmark of occlusive disorders such as atherosclerosis, postangioplasty restenosis, vein graft stenosis, and allograft vasculopathy. Cyclic nucleotides are vital in SMC proliferation and migration, which are regulated by cyclic nucleotide phosphodiesterases (PDEs). OBJECTIVE:
Our goal is to understand the regulation and function of PDEs in SMC pathogenesis of vascular diseases. METHODS ANDRESULTS:
We performed screening for genes differentially expressed in normal contractile versus proliferating synthetic SMCs. We observed that PDE1C expression was low in contractile SMCs but drastically elevated in synthetic SMCs in vitro and in various mouse vascular injury models in vivo. In addition, PDE1C was highly induced in neointimal SMCs of human coronary arteries. More importantly, injury-induced neointimal formation was significantly attenuated by PDE1C deficiency or PDE1 inhibition in vivo. PDE1 inhibition suppressed vascular remodeling of human saphenous vein explants ex vivo. In cultured SMCs, PDE1C deficiency or PDE1 inhibition attenuated SMC proliferation and migration. Mechanistic studies revealed that PDE1C plays a critical role in regulating the stability of growth factor receptors, such as PDGF receptor ß (PDGFRß) known to be important in pathological vascular remodeling. PDE1C interacts with low-density lipoprotein receptor-related protein-1 and PDGFRß, thus regulating PDGFRß endocytosis and lysosome-dependent degradation in an low-density lipoprotein receptor-related protein-1-dependent manner. A transmembrane adenylyl cyclase cAMP-dependent protein kinase cascade modulated by PDE1C is critical in regulating PDGFRß degradation.CONCLUSIONS:
These findings demonstrated that PDE1C is an important regulator of SMC proliferation, migration, and neointimal hyperplasia, in part through modulating endosome/lysosome-dependent PDGFRß protein degradation via low-density lipoprotein receptor-related protein-1.Key words
Full text:
1
Database:
MEDLINE
Main subject:
Myocytes, Smooth Muscle
/
Cyclic Nucleotide Phosphodiesterases, Type 1
/
Neointima
/
Muscle, Smooth, Vascular
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Year:
2015
Type:
Article