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An in silico study on the role of smooth muscle cell migration in neointimal formation after coronary stenting.

ABSTRACT: Excessive migration and proliferation of smooth muscle cells (SMCs) has been observed as a major factor contributing to the development of in-stent restenosis after coronary stenting. Building upon the results from in vivo experiments, we formulated a hypothesis that the speed of the initial tissue re-growth response is determined by the early migration of SMCs from the injured intima. To test this hypothesis, a cellular Potts model of the stented artery is developed where stent struts were deployed at different depths into the tissue. An extreme scenario with a ruptured internal elastic lamina was also considered to study the role of severe injury in tissue re-growth. Based on the outcomes, we hypothesize that a deeper stent deployment results in on average larger fenestrae in the elastic lamina, allowing easier migration of SMCs into the lumen. The data also suggest that growth of the neointimal lesions owing to SMC proliferation is strongly dependent on the initial number of migrated cells, which form an initial condition for the later phase of the vascular repair. This mechanism could explain the in vivo observation that the initial rate of neointima formation and injury score are strongly correlated.

SUBMITTER: Tahir H

PROVIDER: S-EPMC4528603 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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An in silico study on the role of smooth muscle cell migration in neointimal formation after coronary stenting.

Tahir Hannan H Niculescu Ioana I Bona-Casas Carles C Merks Roeland M H RM Hoekstra Alfons G AG

Journal of the Royal Society, Interface 20150701 108

Excessive migration and proliferation of smooth muscle cells (SMCs) has been observed as a major factor contributing to the development of in-stent restenosis after coronary stenting. Building upon the results from in vivo experiments, we formulated a hypothesis that the speed of the initial tissue re-growth response is determined by the early migration of SMCs from the injured intima. To test this hypothesis, a cellular Potts model of the stented artery is developed where stent struts were depl ...[more]

PMID: 26063828

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Project description: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).Our goal is to understand the regulation and function of PDEs in SMC pathogenesis of vascular diseases.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 ? (PDGFR?) known to be important in pathological vascular remodeling. PDE1C interacts with low-density lipoprotein receptor-related protein-1 and PDGFR?, thus regulating PDGFR? 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 PDGFR? degradation.These findings demonstrated that PDE1C is an important regulator of SMC proliferation, migration, and neointimal hyperplasia, in part through modulating endosome/lysosome-dependent PDGFR? protein degradation via low-density lipoprotein receptor-related protein-1.

Dataset Information

An in silico study on the role of smooth muscle cell migration in neointimal formation after coronary stenting.

Publications

An in silico study on the role of smooth muscle cell migration in neointimal formation after coronary stenting.

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