Elevated Expression of Matrix Metalloproteinase-9 not Matrix Metalloproteinase-2 Contributes to Progression of Extracranial Arteriovenous Malformation.

Ting Wei,Emily Miller,Gresham T Richter,James Y Suen,Neslihan Cetin,Haihong Zhang,Teri Moak

doi:10.1038/srep24378

Abstract

Extracranial arteriovenous malformations (AVMs) are rare but dangerous congenital lesions arising from direct arterial-venous shunts without intervening capillaries. Progressive infiltration, expansion, and soft tissue destruction lead to bleeding, pain, debilitation and disfigurement. The pathophysiology of AVMs is not well understood. Matrix Metalloproteinases (MMPs) are thought to play an important role in pathologic processes underlying many diseases. This study investigates the expression of MMP-9 and MMP-2 in aggressive extracranial AVMs. The differential expression of MMP-9 and its regulatory factors is also examined. Herein we demonstrate that mRNA and protein expressions of MMP-9, but not MMP-2, are significantly higher in AVM tissues compared to normal tissues. The serum level of MMP-9, but not MMP-2, is also elevated in AVM patients compared to healthy controls. MMP-9/neutrophil gelatinase-associated lipocalin (NGAL) complex is also significantly increased in AVM tissues. The MMP-9/ tissue inhibitor of metalloproteases-1 (TIMP-1) complex presents as a major form detected in normal tissues. The increased and aberrant expression of MMP-9 and specific MMP-9 forms may help explain the constitutive vascular remodeling and infiltrative nature of these lesions. Specific MMP-9 inhibitors would be a promising treatment for AVMs.

Highlights

Matrix metalloproteinases (MMPs) comprise a family of membrane bound and extracellular zinc-dependent endopeptidases involved in matrix degradation and tissue remodeling, around normally and abnormally developing vasculature
Under non-reducing conditions, blots with anti-Matrix Metalloproteinases (MMPs)-9 antibody revealed four MMP-9 forms with molecular weights of ~250 kDa, ~150 kDa, ~125 kDa and ~92 kDa reproducibly detected in all of our arteriovenous malformations (AVMs) samples. These molecular weights corresponded with MMP-9 multimer, MMP-9/tissue inhibitor of metalloproteases-1 (TIMP-1) complex, MMP-9/neutrophil gelatinase-associated lipocalin (NGAL) complex and MMP-9 monomer, respectively, based on the comigration positions of rhMMP-9 and purified neutrophil MMP-9/NGAL complex
The major form discovered in normal samples was MMP-9/TIMP-1 complex

Summary

Introduction

Matrix metalloproteinases (MMPs) comprise a family of membrane bound and extracellular zinc-dependent endopeptidases involved in matrix degradation and tissue remodeling, around normally and abnormally developing vasculature. Two members of the MMP family, MMP-9 and MMP-2, have been discovered to have a profound impact on angiogenesis and vascular remodeling in malignancies, wound healing, vascular lesions, cardiovascular diseases and inflammatory disorders[4,5,6,7,8]. Their activities are tightly regulated by the enzyme stablizer-neutrophil gelatinase-associated lipocalin (NGAL) and inhibitor-tissue inhibitor of metalloproteases-1 (TIMP-1)[9,10,11,12]. The serum level of MMP-9, but not MMP-2, was increased in AVM patients compared to healthy matched controls

Objectives

Methods

Results

Conclusion