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DOI: 10.1160/TH14-01-0024
Lysyl oxidase (LOX) in vascular remodelling
Insight from a new animal model Financial support: This work was supported by Sociedad Española de Cardiología (Proyecto SEC para Investigación Básica 2012) and the Spanish Ministerio de Economía y Competitividad (MINECO)-Instituto de Salud Carlos III (ISCIII) [grants PI12/01952, SAF2012–40127, RD12/0042/0053 and RD12/0042/0024]. AG and MG were supported by funds provided by Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias (PFIS and Sara Borrell programs respectively) and AMB is supported through the Ramón y Cajal program (RYC-2010–06473).Publication History
Received:
10 January 2014
Accepted after major revision:
06 May 2014
Publication Date:
21 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201404/lookinside/thumbnails/10-1160-th14-01-0024-1.jpg)
Summary
Lysyl oxidase (LOX) is an extracellular matrix-modifying enzyme that seems to play a critical role in vascular remodelling. However, the lack of viable LOX-deficient animal models has been an obstacle to deep in LOX biology. In this study we have developed a transgenic mouse model that over-expresses LOX in vascular smooth muscle cells (VSMC) to clarify whether LOX could regulate VSMC phenotype and vascular remodelling. The SM22 proximal promoter drove the expression of a transgene containing the human LOX cDNA. Two stable transgenic lines, phenotypically indistinguishable, were generated by conventional methods (TgLOX). Transgene expression followed the expected SMC-specific pattern. In TgLOX mice, real-time PCR and immunohistochemistry evidenced a strong expression of LOX in the media from aorta and carotid arteries, coincident with a higher proportion of mature collagen. VSMC isolated from TgLOX mice expressed high levels of LOX pro-enzyme, which was properly secreted and processed into mature and bioactive LOX. Interestingly, cell proliferation was significantly reduced in cells from TgLOX mice. Transgenic VSMC also exhibited low levels of Myh10 (marker of SMC phenotypic switching), PCNA (marker of cell proliferation) and MCP-1, and a weak activation of Akt and ERK1/2 in response to mitogenic stimuli. Accordingly, neointimal thickening induced by carotid artery ligation was attenuated in TgLOX mice that also displayed a reduction in PCNA and MCP-1 immunostaining. Our results give evidence that LOX plays a critical role in vascular remodelling. We have developed a new animal model to study the role of LOX in vascular biology.
¶ The first two authors contributed equally to this work.
‡ The last two authors contributed equally to this work.
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