Basic Pathogenic Mechanisms and Epigenetic Players Promoted by Extracellular Vesicles in Vascular Damage

Abstract

Both progression from the early pathogenic events to clinically manifest cardiovascular diseases (CVD) and cancer impact the integrity of the vascular system. Pathological vascular modifications are affected by interplay between endothelial cells and their microenvironment. Soluble factors, extracellular matrix molecules and extracellular vesicles (EVs) are emerging determinants of this network that trigger specific signals in target cells. EVs have gained attention as package of molecules with epigenetic reversible activity causing functional vascular changes, but their mechanisms are not well understood. Valuable insights have been provided by recent clinical studies, including the investigation of EVs as potential biomarkers of these diseases. In this paper, we review the role and the mechanism of exosomal epigenetic molecules during the vascular remodeling in coronary heart disease as well as in cancer-associated neoangiogenesis.

Keywords: atherosclerosis; biomarkers; cancer; exosome; extracellular vesicle; vascular damage.

Figure 1

Extracellular vesicles and vascular damage. Schematic representation of atherosclerotic EVs. They are produced by the different cell types involved in the mechanism of plaque formation. Harmful EVs can promote atherogenesis by altering vascular integrity, increasing inflammatory response and promoting thrombus formation. On the other hand, beneficial EVs, containing specific ncRNAs, can play athero-protective roles by promoting the repair of damaged endothelium and repressing the activation of inflammatory cells. The EVs interact with target cells via direct fusion, endocytosis or the binding of surface proteins. After this invagination, cytosolic proteins or RNA content-EVs transfer to the extracellular space. In the target cells, ncRNAs (such as lncRNAs, miRNAs, circRNAs) can (A) control nuclear gene expression via epigenetic changes and/or (B) affect protein function.

Figure 2

Schematic representation of EVs involved in different mechanisms of tumor angiogenesis. Tumor cell-derived exosomes carrying biological molecules are involved in various angiogenic mechanisms: (A) sprouting angiogenesis, vessel enlargement, arteriogenesis, vascular mimicry and vessel-cooption favoring tumor growth and pre-metastasis niche formation; (B) Exosomes from malignant cells released locally or at distant sites can induce vessel modifications, with endothelial damage favoring intravasation. Triggering endothelial-mesenchymal transition, which favors endothelial migration at the distal site. Stimulation of extravasation at distant pre-metastatic niche; and (C) Schematic representation of epigenetic mechanisms: 1 DNA methylation; 2 Histone modifications; 3 non-coding RNA targets intracellular mRNA.