Multimerin-2 orchestrates the cross-talk between endothelial cells and pericytes: A mechanism to maintain vascular stability

Albina Fejza; Evelina Poletto; Greta Carobolante; Lucrezia Camicia; Eva Andreuzzi; Alessandra Capuano; Eliana Pivetta; Rosanna Pellicani; Roberta Colladel; Stefano Marastoni; Roberto Doliana; Renato V Iozzo; Paola Spessotto; Maurizio Mongiat

doi:10.1016/j.mbplus.2021.100068

Multimerin-2 orchestrates the cross-talk between endothelial cells and pericytes: A mechanism to maintain vascular stability

Matrix Biol Plus. 2021 May 28:11:100068. doi: 10.1016/j.mbplus.2021.100068. eCollection 2021 Aug.

Affiliations

¹ Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy.
² Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada.
³ Department of Pathology, Anatomy, and Cell Biology, and the Translational Cellular Oncology Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA.

Abstract

Tumor angiogenesis is vital for the growth and development of various solid cancers and as such is a valid and promising therapeutic target. Unfortunately, the use of the currently available anti-angiogenic drugs increases the progression-free survival by only a few months. Conversely, targeting angiogenesis to prompt both vessel reduction and normalization, has been recently viewed as a promising approach to improve therapeutic efficacy. As a double-edged sword, this line of attack may on one side halt tumor growth as a consequence of the reduction of nutrients and oxygen supplied to the tumor cells, and on the other side improve drug delivery and, hence, efficacy. Thus, it is of upmost importance to better characterize the mechanisms regulating vascular stability. In this context, recruitment of pericytes along the blood vessels is crucial to their maturation and stabilization. As the extracellular matrix molecule Multimerin-2 is secreted by endothelial cells and deposited also in juxtaposition between endothelial cells and pericytes, we explored Multimerin-2 role in the cross-talk between the two cell types. We discovered that Multimerin-2 is an adhesion substrate for pericytes. Interestingly, and consistent with the notion that Multimerin-2 is a homeostatic molecule deposited in the later stages of vessel formation, we found that the interaction between endothelial cells and pericytes promoted the expression of Multimerin-2. Furthermore, we found that Multimerin-2 modulated the expression of key cytokines both in endothelial cells and pericytes. Collectively, our findings posit Multimerin-2 as a key molecule in the cross-talk between endothelial cells and pericytes and suggest that the expression of this glycoprotein is required to maintain vascular stability.

Keywords: Ang-2, Angiopeietin-2; Angiogenesis; CD248, cluster of differentiation 248; CD93, cluster of differentiation 93; ECM, extracellular matrix; EDEN, EMI Domain ENdowed; Extracellular matrix; HB-EGF, heparin binding epidermal growth factor; HBVP, human brain vascular pericytes; HDMEC, human dermal vascular endothelial cells; HUVEC, human umbilical vein endothelial cells; Notch-3-R, Notch Receptor 3; PDGF, platelet-derived growth factor; VEGFA, vascular endothelial growth factor A; VEGFR2, vascular endothelial growth factor receptor 2; VSMCs, vascular smooth muscle cells; Vascular stability.