Plasma fibronectin deficiency impedes atherosclerosis progression and fibrous cap formation

Ina Rohwedder,Reinhard Fässler,Pontus Dunér,Jan Nilsson,Oliver Soehnlein,Karsten Beckmann,Eva Bengtsson,Eloi Montanez

doi:10.1002/emmm.201200237

Abstract

Atherosclerotic lesions are asymmetric focal thickenings of the intima of arteries that consist of lipids, various cell types and extracellular matrix (ECM). These lesions lead to vascular occlusion representing the most common cause of death in the Western world. The main cause of vascular occlusion is rupture of atheromatous lesions followed by thrombus formation. Fibronectin (FN) is one of the earliest ECM proteins deposited at atherosclerosis-prone sites and was suggested to promote atherosclerotic lesion formation. Here, we report that atherosclerosis-prone apolipoprotein E-null mice lacking hepatocyte-derived plasma FN (pFN) fed with a pro-atherogenic diet display dramatically reduced FN depositions at atherosclerosis-prone areas, which results in significantly smaller and fewer atherosclerotic plaques. However, the atherosclerotic lesions from pFN-deficient mice lacked vascular smooth muscle cells and failed to develop a fibrous cap. Thus, our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion.

Highlights

Atherosclerosis is a progressive inflammatory disease of large arteries characterized by an accumulation of lipids and extracellular matrix (ECM) proteins in the affected vessel wall (Lusis, 2000)
Our results demonstrate that while FN worsens the course of atherosclerosis by increasing the atherogenic plaque area, it promotes the formation of the protective fibrous cap, which in humans prevents plaques rupture and vascular occlusion
Whether FN serves a similar function in vivo and whether the FN depositions are derived from the circulation or from infiltrating monocytes and/or resident endothelial cells (EC)

Summary

Introduction

Atherosclerosis is a progressive inflammatory disease of large arteries characterized by an accumulation of lipids and extracellular matrix (ECM) proteins in the affected vessel wall (Lusis, 2000). Macrophage-derived chemoattractants induce the migration of vascular smooth muscle cells (vSMC) from the vessel wall into the lesion, where they secrete ECM proteins resulting in lesion growth and the formation of the ‘fibrous cap’ that encloses the lipid-rich core (Newby & Zaltsman, 1999). The rupture of fibrous caps represents an injured vessel surface and triggers adhesion and activation of platelets, which can culminate in thrombus formation and eventually myocardial infarction or stroke (Lusis, 2000). Vulnerable plaques have thin fibrous caps and contain elevated numbers of inflammatory cells (Newby, 2007; Newby et al, 2009)

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