Yujun Cai1, David J Nagel1, Qian Zhou1, Katherine D Cygnar1, Haiqing Zhao1, Faqian Li1, Xinchun Pi1, Peter A Knight1, Chen Yan2. 1. 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.). 2. 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.
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 AND 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.
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 AND 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 mousevascular 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 PDE1Cdeficiency or PDE1 inhibition in vivo. PDE1 inhibition suppressed vascular remodeling of human saphenous vein explants ex vivo. In cultured SMCs, PDE1Cdeficiency 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: Walter E Knight; Si Chen; Yishuai Zhang; Masayoshi Oikawa; Meiping Wu; Qian Zhou; Clint L Miller; Yujun Cai; Deanne M Mickelsen; Christine Moravec; Eric M Small; Junichi Abe; Chen Yan Journal: Proc Natl Acad Sci U S A Date: 2016-10-20 Impact factor: 11.205
Authors: Michael T Yarboro; Matthew D Durbin; Jennifer L Herington; Elaine L Shelton; Tao Zhang; Cris G Ebby; Jason Z Stoller; Ronald I Clyman; Jeff Reese Journal: Semin Perinatol Date: 2018-05-10 Impact factor: 3.300
Authors: Toru Hashimoto; Grace E Kim; Richard S Tunin; Tolulope Adesiyun; Steven Hsu; Ryo Nakagawa; Guangshuo Zhu; Jennifer J O'Brien; Joseph P Hendrick; Robert E Davis; Wei Yao; David Beard; Helen R Hoxie; Lawrence P Wennogle; Dong I Lee; David A Kass Journal: Circulation Date: 2018-10-30 Impact factor: 29.690