Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration

Williams, Helen, Mill, Carina AE, Monk, Bethan A, Hulin-Curtis, Sarah L ORCID: 0000-0003-0889-964X, Johnson, Jason L and George, Sarah J (2016) Wnt2 and WISP-1/CCN4 Induce Intimal Thickening via Promotion of Smooth Muscle Cell Migration. Arteriosclerosis, Thrombosis, and Vascular Biology, 36 (7). pp. 1417-1424. doi:10.1161/ATVBAHA.116.307626

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Text 14148 Williams, Mill, Monk, Hulin-Curtis, Johnson, George (2016) Wnt2 and WISP-1 - CCN4 induce intimal thickening via promotion of smooth muscle cell migration.pdf - Accepted Version Available under License Creative Commons Attribution 4.0. Download (1MB) | Preview

Abstract

Objective: Increased vascular smooth muscle cell (VSMC) migration leads to intimal thickening which acts as a soil for atherosclersosis, as well as causing coronary artery restenosis after stenting and vein graft failure. Investigating factors involved in VSMC migration may enable us to reduce intimal thickening and improve patient outcomes. In this study, we determined whether Wnt proteins regulate VSMC migration and thereby intimal thickening. Approach and Results: Wnt2 mRNA and protein expression were specifically increased in migrating mouse aortic VSMCs. Moreover, VSMC migration was induced by recombinant Wnt2 in vitro. Addition of recombinant Wnt2 protein increased Wnt1-inducible signaling pathway protein-1 (WISP-1) mRNA by ≈1.7-fold, via β-catenin/T-cell factor signaling, whereas silencing RNA knockdown of Wnt-2 reduced WISP-1 mRNA by ≈65%. Treatment with rWISP-1 significantly increased VSMC migration by ≈1.5-fold, whereas WISP-1 silencing RNA knockdown reduced migration by ≈40%. Wnt2 and WISP-1 effects were integrin-dependent and not additive, indicating that Wnt2 promoted VSMC migration via WISP-1. Additionally, Wnt2 and WISP-1 were significantly increased and colocated in human coronary arteries with intimal thickening. Reduced Wnt2 and WISP-1 levels in mouse carotid arteries from Wnt2+/− and WISP-1−/− mice, respectively, significantly suppressed intimal thickening in response to carotid artery ligation. In contrast, elevation of plasma WISP-1 via an adenovirus encoding WISP-1 significantly increased intimal thickening by ≈1.5-fold compared with mice receiving control virus. Conclusions: Upregulation of Wnt2 expression enhanced WISP-1 and promoted VSMC migration and thereby intimal thickening. As novel regulators of VSMC migration and intimal thickening, Wnt2 or WISP-1 may provide a potential therapy for restenosis and vein graft failure.

Item Type:	Article
Article Type:	Article
Uncontrolled Keywords:	Intimal thickening; Restenosis; Smooth muscle cell migration; WISP-1/CCN4; Wnt2
Subjects:	R Medicine > R Medicine (General)
Divisions:	Schools and Research Institutes > School of Education and Science
Research Priority Areas:	Health, Life Sciences, Sport and Wellbeing
Depositing User:	Sarah Curtis
Date Deposited:	18 Jun 2024 10:05
Last Modified:	18 Jun 2024 10:15
URI:	https://eprints.glos.ac.uk/id/eprint/14148

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