Transglutaminase 2 Promotes PDGF-Mediated Activation of PDGFR/Akt1 and β-Catenin Signaling in Vascular Smooth Muscle Cells and Supports Neointima Formation
Year: 2014
Type: article
Abstract: BACKGROUND: Phenotypic switch of vascular smooth muscle cells (VSMCs) accompanies neointima formation and associates with vascular diseases. Platelet-derived growth factor (PDGF)-induced activation of PDGFR/Akt1 and β-catenin signaling pathways in VSMCs has been implicated in vessel occlusion. Transglutaminase 2 (TG2) regulates these pathways and its levels are increased in the neointima. OBJECTIVE: The aim of this study was to evaluate the role of TG2 in PDGF/β-catenin signaling cross-talk and assess its contribution to neointima. METHODS: Aortic VSMCs from wild-type and TG2 knockout mice were tested in vitro for levels of VSMC markers, proliferation, migration and PDGF-induced activation of PDGFR/Akt1 and β-catenin pathways. Neointima in these mice was studied ex vivo in coronary vessels using a heart slice model and in vivo using a carotid artery ligation model. RESULTS: Genetic deletion of TG2 attenuated the PDGF-induced phenotypic switch of aortic VSMCs, reduced their proliferation and migration rates, and inhibited PDGF-induced activation of PDGFR/Akt1 and β-catenin pathways in both ex vivo and in vivo neointima models. Importantly, genetic deletion of TG2 also markedly attenuated vessel occlusion. CONCLUSIONS: TG2 promotes neointima formation by mediating the PDGF-induced activation of the PDGFR/Akt1 and β-catenin pathways in VSMCs. This study identifies TG2 as a potential therapeutic target for blocking neointima in blood vessels.
Source: Journal of Vascular Research
DOI: 10.1159/000369461
Institution: University of Maryland, Baltimore
Language: English
Topic: TGF-β signaling in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2006853487