Mutual interaction between endothelial cells and mural cells enhances BMP9 signaling in endothelial cells.

Yuki Tachida,Nanae Izumi,Hideki Kobayashi,Toyo Sakurai

doi:10.1242/bio.020503

Abstract

ABSTRACTHereditary hemorrhagic telangiectasia is characterized by the formation of abnormal vascular networks and caused by the mutation of genes involved in BMP9 signaling. It is also known that the interaction between endothelial cells (ECs) and mural cells (MCs) is critical to maintain vessel integrity. However, it has not yet fully been uncovered whether the EC–MC interaction affects BMP9 signaling or not. To elucidate this point, we analyzed BMP9 signaling in a co-culture of several types of human primary culture ECs and MCs. The co-culture activated the Notch pathway in both types of cells in a co-culture- and BMP9-dependent manner. In HUVECs, the genes induced by BMP9 were significantly and synergistically induced in the presence of pericytes, fibroblasts or mesenchymal stem cells. The synergistic induction was greatly reduced in a non-contact condition. In fibroblasts, PDGFRB expression was potently induced in the presence of HUVECs, and BMP9 additively increased this response. Taken together, these results suggest that the EC–MC interaction potentiates BMP9 signaling both in ECs and MCs and plays a critical role in the maintenance of proper vessel functions.

Highlights

An increasing amount of evidence has shown that the mutual interaction between endothelial cells (ECs) and mural cells (MCs), microvascular periendothelial mesenchymal cells that cover ECs in vessels, is pivotal to the maintenance of vessel integrity (Armulik et al, 2011; Gaengel et al, 2009; Geevarghese and Herman, 2014; van Dijk et al, 2015)
Notch pathway is synergistically activated by BMP9 and the EC–MC interaction To evaluate the effects of the interaction between endothelial cells (ECs) and mural cells (MCs) on the bone morphogenic protein-9 (BMP9) pathway, we analyzed the BMP9 signaling in the co-culture of several types of human primary culture ECs and MCs
After BMP9 stimulation, the ECs and MCs were separated by using CD31-magnetic beads and gene expression in each of the cells was evaluated by quantitative PCR (Fig. 1A)

Summary

Introduction

An increasing amount of evidence has shown that the mutual interaction between endothelial cells (ECs) and mural cells (MCs), microvascular periendothelial mesenchymal cells that cover ECs in vessels, is pivotal to the maintenance of vessel integrity (Armulik et al, 2011; Gaengel et al, 2009; Geevarghese and Herman, 2014; van Dijk et al, 2015). The interaction between ECs and MCs regulates various cellular functions and responses of each cell, such as gene expression, cell proliferation, and cell differentiation, and is regulated in a direct, paracrine, and autocrine fashion Notch signaling plays an important role in the differentiation, maturation, and function of vascular smooth muscle cells (vSMCs) (Fouillade et al, 2012). Signals from ECs to MCs are essential to maintain adequate vessel function

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Conclusion