Abstract 165: cAMP-Phosphodiesterase 1C Regulates Neointimal Hyperplasia by Controlling Platelet-Derived Growth Factor Receptor ß Degradation via the Endosome-Lysosome Pathway

Abstract

Neointimal hyperplasia is associated with the development of diverse vascular diseases such as atherosclerosis, vein bypass graft disease and restenosis after percutaneous coronary interventions. Vascular injury-mediated neointimal hyperplasia involves the phenotypic modulation, migration and proliferation of vascular smooth muscle cells (VSMCs). Cyclic nucleotide is vital in regulating VSMC migration and proliferation, which are controlled by cyclic nucleotide phosphodiesterase (PDE) isozymes. To identify the regulation and function of PDEs in VSMC pathogenesis of vascular diseases, we performed systematic screening for all 22 known PDE genes in normal contractile VSMCs and proliferating synthetic VSMCs. Interestingly, we observed that expression of PDE1C was very low in normal contractile VSMCs but drastically elevated in synthetic VSMCs in vitro as well as in vivo in various mouse models of vascular injuries, including carotid artery ligation, femoral artery wire injury and vein bypass graft. Consistently, PDE1C is also highly induced in VSMCs in neointimal lesion of human coronary artery. More importantly, injury-induced neointimal formation was significantly attenuated in pde1c-deficient mice or by perivascular administration of PDE1 inhibitor. Furthermore, PDE1 inhibition also reduced the spontaneous vascular remodeling of human saphenous vein explant in an ex vivo culture model. Mechanistic studies revealed that PDE1C plays a critical role in regulating the stability of PDGF receptor beta (PDGFR-β). We found that PDE1C knockdown or inhibition markedly decreased the levels of PDGFR-β protein but not mRNA, which was blocked by endosome and lysosome inhibitors. Furthermore, PDE1C inhibition is capable of promoting PDGFR-β internalization and attenuating PDGFR-β membrane accumulation. Finally, we found that PDE1C co-localized with PDGFR-β on cell membrane, which was able to regulate PDGFR-β protein degradation through modulating a transmembrane adenylyl cyclase-cAMP-PKA signaling. Taken together, our present data demonstrated that PDE1C plays a critical role in regulating VSMC proliferation and neointimal hyperplasia, in part, through promoting endosome/lysosome dependent PDGFR-β protein degradation.