{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T06:00:40Z","timestamp":1791352840274,"version":"4.3.1"},"reference-count":63,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2015,3,27]]},"abstract":"<jats:sec>\n            <jats:title>\n              <jats:underline>Rationale:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>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).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Objective:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>Our goal is to understand the regulation and function of PDEs in SMC pathogenesis of vascular diseases.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Methods and Results:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>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 \u03b2 (PDGFR\u03b2) known to be important in pathological vascular remodeling. PDE1C interacts with low-density lipoprotein receptor\u2013related protein-1 and PDGFR\u03b2, thus regulating PDGFR\u03b2 endocytosis and lysosome-dependent degradation in an low-density lipoprotein receptor\u2013related protein-1\u2013dependent manner. A transmembrane adenylyl cyclase cAMP-dependent protein kinase cascade modulated by PDE1C is critical in regulating PDGFR\u03b2 degradation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>\n              <jats:underline>Conclusions:<\/jats:underline>\n            <\/jats:title>\n            <jats:p>These findings demonstrated that PDE1C is an important regulator of SMC proliferation, migration, and neointimal hyperplasia, in part through modulating endosome\/lysosome-dependent PDGFR\u03b2 protein degradation via low-density lipoprotein receptor\u2013related protein-1.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circresaha.116.304408","type":"journal-article","created":{"date-parts":[[2015,1,22]],"date-time":"2015-01-22T03:24:19Z","timestamp":1421897059000},"page":"1120-1132","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":95,"title":["Role of cAMP-Phosphodiesterase 1C Signaling in Regulating Growth Factor Receptor Stability, Vascular Smooth Muscle Cell Growth, Migration, and Neointimal Hyperplasia"],"prefix":"10.1161","volume":"116","author":[{"given":"Yujun","family":"Cai","sequence":"first","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Nagel","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qian","family":"Zhou","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine D.","family":"Cygnar","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiqing","family":"Zhao","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faqian","family":"Li","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinchun","family":"Pi","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"Knight","sequence":"additional","affiliation":[{"name":"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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Yan","sequence":"additional","affiliation":[{"name":"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; 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