Hypoxia/reperfusion predisposes to atherosclerosis.

Richard Finsterwalder,Peter Petzelbauer,Heide Leb,Dominik Wiedemann,José Basílio,Minu Karthika Ganesan,Irene Lang,Andreas Habertheuer,Milica Krunic,Gianfranco Pintus

doi:10.1371/journal.pone.0205067

Abstract

Surgical interventions on blood vessels bear a risk for intimal hyperplasia and atherosclerosis as a consequence of injury. A specific feature of intimal hyperplasia is the loss of vascular smooth muscle cell (VSMC) differentiation gene expression. We hypothesized that immediate responses following injury induce vascular remodeling. To differentiate injury due to trauma, reperfusion and pressure changes we analyzed vascular responses to carotid artery bypass grafting in mice compared to transient ligation. As a control, the carotid artery was surgically laid open only. In both, bypass or ligation models, the inflammatory responses were transient, peaking after 6h, whereas the loss of VSMC differentiation gene expression persisted. Extended time kinetics showed that transient carotid artery ligation was sufficient to induce a persistent VSMC phenotype change throughout 28 days. Transient arterial ligation in ApoE knockout mice resulted in atherosclerosis in the transiently ligated vascular segment but not on the not-ligated contralateral side. The VSMC phenotype change could not be prevented by anti-TNF antibodies, Sorafenib, Cytosporone B or N-acetylcysteine treatment. Surgical interventions involving hypoxia/reperfusion are sufficient to induce VSMC phenotype changes and vascular remodeling. In situations of a perturbed lipid metabolism this bears the risk to precipitate atherosclerosis.

Highlights

Arteries and veins consist of 3 layers; the adventitia, largely constituted of connective tissue and fibroblasts, the media mainly containing vascular smooth muscle cells (VSMCs) and the intima
Separated from the media by the internal elastic lamina, the intima consists of loose connective tissue intermingled with few VSMCs and a monolayer of endothelial cells (ECs) resting on a basal membrane forming the interface to the bloodstream
To screen for immediate changes in a vessel subjected to bypass grafting, a vein graft model was used, which consistently induces intimal hyperplasia within 28 days.[16] mRNA sequencing analysis was performed on bypass grafts obtained 1, 6 and 24h after grafting to monitor the immediate reaction of the tissue to injury

Summary

Introduction

Arteries and veins consist of 3 layers; the adventitia, largely constituted of connective tissue and fibroblasts, the media mainly containing vascular smooth muscle cells (VSMCs) and the intima. Distinctions should be made between acute versus chronic injury, the latter occurring with aging; age-associated vascular remodeling is a risk factor for atherosclerosis in humans.[2,3,4] Excessive IH can cause morbidity by narrowing the vessel lumen or by priming the vessel for atherosclerosis.[5] This is of special importance for patients subjected to coronary revascularization procedures, such as bypass grafting or stenting since the long term patency is significantly limited by negative vessel remodeling.[1]

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Conclusion