Paracrine Shear-Stress-Dependent Signaling from Endothelial Cells Affects Downstream Endothelial Function and Inflammation.

Fabio Bertani,Maria Talmon,Maria Dolores Corrado,Luigia Grazia Fresu,Dalila Di Francesco,Francesca Boccafoschi

doi:10.3390/ijms222413300

Abstract

Cardiovascular diseases (CVDs), mainly ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and major contributors to disability worldwide. Despite their heterogeneity, almost all CVDs share a common feature: the endothelial dysfunction. This is defined as a loss of functionality in terms of anti-inflammatory, anti-thrombotic and vasodilatory abilities of endothelial cells (ECs). Endothelial function is greatly ensured by the mechanotransduction of shear forces, namely, endothelial wall shear stress (WSS). Low WSS is associated with endothelial dysfunction, representing the primary cause of atherosclerotic plaque formation and an important factor in plaque progression and remodeling. In this work, the role of factors released by ECs subjected to different magnitudes of shear stress driving the functionality of downstream endothelium has been evaluated. By means of a microfluidic system, HUVEC monolayers have been subjected to shear stress and the conditioned media collected to be used for the subsequent static culture. The results demonstrate that conditioned media retrieved from low shear stress experimental conditions (LSS-CM) induce the downregulation of endothelial nitric oxide synthase (eNOS) expression while upregulating peripheral blood mononuclear cell (PBMC) adhesion by means of higher levels of adhesion molecules such as E-selectin and ICAM-1. Moreover, LSS-CM demonstrated a significant angiogenic ability comparable to the inflammatory control media (TNFα-CM); thus, it is likely related to tissue suffering. We can therefore suggest that ECs stimulated at low shear stress (LSS) magnitudes are possibly involved in the paracrine induction of peripheral endothelial dysfunction, opening interesting insights into the pathogenetic mechanisms of coronary microvascular dysfunction.

Highlights

Described in 1865 by the Swiss anatomist Wilhelm His [1,2] as a mere inert barrier separating blood from the surrounding tissues, from the 1970s the endothelium has been increasingly associated with vascular performance
This multi-component complex consists of platelet endothelial cell adhesion molecule 1 (PECAM-1), vascular endohelial-cadherin and vascular endothelial growth factor receptor 2 (VEGFR-2), which have been indicated to be responsible for the activation of shear-response pathways ranging from cell alignment to endothelial function and dysfunction [6,9,10,11]
We demonstrated that dysfunctional endothelial cells could affect downstream endothelium playing a major role in the regulation of adhesion molecule expression and angiogenesis

Summary

Introduction

Described in 1865 by the Swiss anatomist Wilhelm His [1,2] as a mere inert barrier separating blood from the surrounding tissues, from the 1970s the endothelium has been increasingly associated with vascular performance. It has an essential role in maintaining blood fluidity, driving platelet aggregation and vascular tone; it is a major actor in the regulation of immune response, inflammation, angiogenesis, and, lastly, it is a metabolizing and endocrine organ [3]. This multi-component complex consists of platelet endothelial cell adhesion molecule 1 (PECAM-1), vascular endohelial-cadherin and vascular endothelial growth factor receptor 2 (VEGFR-2), which have been indicated to be responsible for the activation of shear-response pathways ranging from cell alignment to endothelial function and dysfunction [6,9,10,11]

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Discussion

Conclusion