Roles of fibronectin isoforms in neonatal vascular development and matrix integrity.

Heena Kumra,Deane F Mosher,Takao Sakai,Amani Hassan,Laetitia Sabatier,Dieter P Reinhardt,Jürgen Brinckmann,Kenneth Yamada

doi:10.1371/journal.pbio.2004812

Abstract

Fibronectin (FN) exists in two forms—plasma FN (pFN) and cellular FN (cFN). Although the role of FN in embryonic blood vessel development is well established, its function and the contribution of individual isoforms in early postnatal vascular development are poorly understood. Here, we employed a tamoxifen-dependent cFN inducible knockout (cFN iKO) mouse model to study the consequences of postnatal cFN deletion in smooth muscle cells (SMCs), the major cell type in the vascular wall. Deletion of cFN influences collagen deposition but does not affect life span. Unexpectedly, pFN translocated to the aortic wall in the cFN iKO and in control mice, possibly rescuing the loss of cFN. Postnatal pFN deletion did not show a histological aortic phenotype. Double knockout (dKO) mice lacking both, cFN in SMCs and pFN, resulted in postnatal lethality. These data demonstrate a safeguard role of pFN in vascular stability and the dispensability of the individual FN isoforms in postnatal vascular development. Complete absence of FNs in the dKOs resulted in a disorganized tunica media of the aortic wall. Matrix analysis revealed common and differential roles of the FN isoforms in guiding the assembly/deposition of elastogenic extracellular matrix (ECM) proteins in the aortic wall. In addition, we determined with two cell culture models that that the two FN isoforms acted similarly in supporting matrix formation with a greater contribution from cFN. Together, these data show that pFN exerts a critical role in safeguarding vascular organization and health, and that the two FN isoforms function in an overlapping as well as distinct manner to maintain postnatal vascular matrix integrity.

Highlights

Fibronectin (FN) is an abundant and ubiquitously expressed protein in the extracellular matrix (ECM) of various connective tissues as well as in blood of vertebrates [1,2]
Fibronectin is important for the development of blood vessels before birth, but whether it is continuously required for blood vessel homeostasis from birth to adulthood is unknown
FNs occur in two principal forms, the soluble plasma FN circulating in the blood and the cellular FN, which polymerizes into insoluble fibers in the ECM of tissues, including blood vessels [7]. pFN is synthesized exclusively in the liver by hepatocytes [8,9] and shows a relatively simple splicing pattern lacking the extra domain-A (EDA) and extra domain-B (EDB) domains, forms with and without the V region exist [10]

Summary

Introduction

Fibronectin (FN) is an abundant and ubiquitously expressed protein in the extracellular matrix (ECM) of various connective tissues as well as in blood of vertebrates [1,2]. Alternative splicing occurs within the central array of FNIII repeats, leading to either inclusion or exclusion of the FNIII extra domain-A (EDA) and extra domain-B (EDB) domains (Fig 1A). Another region of alternative splicing occurs towards the C-terminus of this array, the V region [6]. FNs occur in two principal forms, the soluble plasma FN (pFN) circulating in the blood and the cellular FN (cFN), which polymerizes into insoluble fibers in the ECM of tissues, including blood vessels [7]. The cFN consists of a much larger and more heterogeneous group of isoforms, with either EDA, EDB, or both domains present [4,13]

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