The angiostatic molecule Multimerin 2 is processed by MMP-9 to allow sprouting angiogenesis

Eva Andreuzzi, Roberta Colladel, Rosanna Pellicani, Giulia Tarticchio, Renato Cannizzaro, Paola Spessotto, Benedetta Bussolati, Alessia Brossa, Paolo De Paoli, Vincenzo Canzonieri, Renato V. Iozzo, Alfonso Colombatti, Maurizio Mongiat

Research output: Contribution to journalArticle

Abstract

Angiogenesis is a crucial process occurring under physiological and pathological conditions, including cancer. The development of blood vessels is tightly regulated by a plethora of cytokines, endothelial cell (EC) receptors and extracellular matrix (ECM) components. In this context, we have shown that Multimerin 2 (MMRN2), an ECM molecule specifically secreted by ECs, exerts angiostatic functions by binding VEGFA and other pro-angiogenic cytokines. Here, we demonstrate that during angiogenic stimuli MMRN2 mRNA levels significantly decrease. Furthermore, we provide evidence that MMRN2 is processed by matrix metalloproteinases (MMPs) including MMP-9 and, to a lesser degree, by MMP-2. This proteolytic cleavage correlates with an increased migration of ECs. Accordingly, MMRN2 down-regulation is associated with an increased number of EC pseudopodia at the migrating front and this effect is attenuated using specific MMP-9 inhibitors. The down-modulation of MMRN2 occurs also in the context of tumor-associated angiogenesis. Immunofluorescence performed on tumor sections indicate a broad co-localization of MMP-9 and MMRN2, suggesting that the molecule may be extensively remodeled during tumor angiogenesis. Given the altered expression in tumors and the key role of MMRN2 in blood vessel function, we postulate that analyses of its expression may serve as a marker to predict the efficacy of the treatments. In conclusion, these data further support the role of MMRN2 as a key molecule regulating EC function and sprouting angiogenesis.

Original languageEnglish
Pages (from-to)40-53
Number of pages14
JournalMatrix Biology
Volume64
DOIs
Publication statusPublished - Dec 1 2017

Keywords

  • Angiogenesis
  • Endothelial cells
  • Tumor microenvironment

ASJC Scopus subject areas

  • Molecular Biology

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