title: Role of cAMP-phosphodiesterase 1C signaling in regulating growth factor receptor stability, vascular smooth muscle cell growth, migration, and neointimal hyperplasia.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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 β (PDGFRβ) known to be important in pathological vascular remodeling. PDE1C interacts with low-density lipoprotein receptor-related protein-1 and PDGFRβ, thus regulating PDGFRβ 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 PDGFRβ 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 PDGFRβ protein degradation via low-density lipoprotein receptor-related protein-1.
authors.affiliation: From the Department of Medicine, Aab Cardiovascular Research Institute (Y.C., D.J.N., Q.Z., C.Y.), Department of Pathology and Laboratory Medicine (F.L.), and Department of Surgery (P.A.K.), School of Medicine and Dentistry, University of Rochester, NY; Department of Biology, Johns Hopkins University, Baltimore, MD (K.D.C., H.Z.); and Department of Medicine, Athero and Lipo Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P.).
authors.forename: Yujun
authors.initials: Y
authors.lastname: Cai
authors.affiliation: From the Department of Medicine, Aab Cardiovascular Research Institute (Y.C., D.J.N., Q.Z., C.Y.), Department of Pathology and Laboratory Medicine (F.L.), and Department of Surgery (P.A.K.), School of Medicine and Dentistry, University of Rochester, NY; Department of Biology, Johns Hopkins University, Baltimore, MD (K.D.C., H.Z.); and Department of Medicine, Athero and Lipo Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P.).
authors.forename: David J
authors.initials: DJ
authors.lastname: Nagel
authors.affiliation: From the Department of Medicine, Aab Cardiovascular Research Institute (Y.C., D.J.N., Q.Z., C.Y.), Department of Pathology and Laboratory Medicine (F.L.), and Department of Surgery (P.A.K.), School of Medicine and Dentistry, University of Rochester, NY; Department of Biology, Johns Hopkins University, Baltimore, MD (K.D.C., H.Z.); and Department of Medicine, Athero and Lipo Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P.).
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: From the Department of Medicine, Aab Cardiovascular Research Institute (Y.C., D.J.N., Q.Z., C.Y.), Department of Pathology and Laboratory Medicine (F.L.), and Department of Surgery (P.A.K.), School of Medicine and Dentistry, University of Rochester, NY; Department of Biology, Johns Hopkins University, Baltimore, MD (K.D.C., H.Z.); and Department of Medicine, Athero and Lipo Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P.).
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Cygnar
authors.affiliation: From the Department of Medicine, Aab Cardiovascular Research Institute (Y.C., D.J.N., Q.Z., C.Y.), Department of Pathology and Laboratory Medicine (F.L.), and Department of Surgery (P.A.K.), School of Medicine and Dentistry, University of Rochester, NY; Department of Biology, Johns Hopkins University, Baltimore, MD (K.D.C., H.Z.); and Department of Medicine, Athero and Lipo Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P.).
authors.forename: Haiqing
authors.initials: H
authors.lastname: Zhao
authors.affiliation: From the Department of Medicine, Aab Cardiovascular Research Institute (Y.C., D.J.N., Q.Z., C.Y.), Department of Pathology and Laboratory Medicine (F.L.), and Department of Surgery (P.A.K.), School of Medicine and Dentistry, University of Rochester, NY; Department of Biology, Johns Hopkins University, Baltimore, MD (K.D.C., H.Z.); and Department of Medicine, Athero and Lipo Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P.).
authors.forename: Faqian
authors.initials: F
authors.lastname: Li
authors.affiliation: From the Department of Medicine, Aab Cardiovascular Research Institute (Y.C., D.J.N., Q.Z., C.Y.), Department of Pathology and Laboratory Medicine (F.L.), and Department of Surgery (P.A.K.), School of Medicine and Dentistry, University of Rochester, NY; Department of Biology, Johns Hopkins University, Baltimore, MD (K.D.C., H.Z.); and Department of Medicine, Athero and Lipo Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P.).
authors.forename: Xinchun
authors.initials: X
authors.lastname: Pi
authors.affiliation: From the Department of Medicine, Aab Cardiovascular Research Institute (Y.C., D.J.N., Q.Z., C.Y.), Department of Pathology and Laboratory Medicine (F.L.), and Department of Surgery (P.A.K.), School of Medicine and Dentistry, University of Rochester, NY; Department of Biology, Johns Hopkins University, Baltimore, MD (K.D.C., H.Z.); and Department of Medicine, Athero and Lipo Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P.).
authors.forename: Peter A
authors.initials: PA
authors.lastname: Knight
authors.affiliation: From the Department of Medicine, Aab Cardiovascular Research Institute (Y.C., D.J.N., Q.Z., C.Y.), Department of Pathology and Laboratory Medicine (F.L.), and Department of Surgery (P.A.K.), School of Medicine and Dentistry, University of Rochester, NY; Department of Biology, Johns Hopkins University, Baltimore, MD (K.D.C., H.Z.); and Department of Medicine, Athero and Lipo Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX (X.P.). chen_yan@urmc.rochester.edu.
authors.forename: Chen
authors.initials: C
authors.lastname: Yan
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000201:enzymology / Q000473:pathology; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology; D004790:Enzyme Induction; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008247:Lysosomes / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000201:enzymology*; D058426:Neointima / Q000201:enzymology* / Q000503:physiopathology; D025941:Protein Interaction Mapping; D055550:Protein Stability; D059748:Proteolysis; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
chemical_list: C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000242:Cyclic AMP; D020797:Receptor, Platelet-Derived Growth Factor beta; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; C517272:PDE1C protein, human; C517273:Pde1C protein, mouse
keywords: cyclic nucleotide phosphodiesterases, type 1C; neointima formation; smooth muscle cell