Multimerin-2 maintains vascular stability and permeability

Rosanna Pellicani, Evelina Poletto, Eva Andreuzzi, Alice Paulitti, Roberto Doliana, Dario Bizzotto, Paola Braghetta, Roberta Colladel, Giulia Tarticchio, Patrizia Sabatelli, Francesco Bucciotti, Giorgio Bressan, Renato V. Iozzo, Alfonso Colombatti, Paolo Bonaldo, Maurizio Mongiat

Research output: Contribution to journalArticle

Abstract

Multimerin-2 is an extracellular matrix glycoprotein and member of the elastin microfibril interface-located (EMILIN) family of proteins. Multimerin-2 is deposited along blood vessels and we previously demonstrated that it regulates the VEGFA/VEGFR2 signaling axis and angiogenesis. However, its role in modulating vascular homeostasis remains largely unexplored. Here we identified Multimerin-2 as a key molecule required to maintain vascular stability. RNAi knockdown of Multimerin-2 in endothelial cells led to cell-cell junctional instability and increased permeability. Mechanistically cell-cell junction dismantlement occurred through the phosphorylation of VEGFR2 at Tyr951, activation of Src and phosphorylation of VE-cadherin. To provide an in vivo validation for these in vitro effects, we generated Multimerin-2−/− (Mmrn2−/−) mice. Although Mmrn2−/− mice developed normally and displayed no gross abnormalities, endothelial cells displayed cell junctional defects associated with increased levels of VEGFR2 phospho-Tyr949 (the murine counterpart of human Tyr951), impaired pericyte recruitment and increased vascular leakage. Of note, tumor associated vessels were defective in Mmrn2−/− mice, with increased number of small and often collapsed vessels, concurrent with a significant depletion of pericytic coverage. Consequently, the Mmrn2−/− vessels were less perfused and leakier, leading to increased tumor hypoxia. Chemotherapy efficacy was markedly impaired in Mmrn2−/− mice and this was associated with poor drug delivery to the tumor xenografts. Collectively, our findings demonstrate that Multimerin-2 is required for proper vessel homeostasis and stabilization, and unveil the possibility to utilize expression levels of this glycoprotein in predicting chemotherapy efficacy.

Original languageEnglish
Pages (from-to)epub
JournalMatrix Biology
DOIs
Publication statusAccepted/In press - Jan 1 2019

Keywords

  • angiogenesis
  • extracellular matrix
  • tumor growth
  • tumor microenvironment
  • vascular homeostasis

ASJC Scopus subject areas

  • Molecular Biology

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  • Cite this

    Pellicani, R., Poletto, E., Andreuzzi, E., Paulitti, A., Doliana, R., Bizzotto, D., Braghetta, P., Colladel, R., Tarticchio, G., Sabatelli, P., Bucciotti, F., Bressan, G., Iozzo, R. V., Colombatti, A., Bonaldo, P., & Mongiat, M. (Accepted/In press). Multimerin-2 maintains vascular stability and permeability. Matrix Biology, epub. https://doi.org/10.1016/j.matbio.2019.08.002