Endothelial Extracellular Vesicles in Pulmonary Function and Disease

Abstract

The pulmonary vascular endothelium is involved in the pathogenesis of acute and chronic lung diseases. Endothelial cell (EC)-derived products such as extracellular vesicles (EVs) serve as EC messengers that mediate inflammatory as well as cytoprotective effects. EC-EVs are a broad term, which encompasses exosomes and microvesicles of endothelial origin. EVs are comprised of lipids, nucleic acids, and proteins that reflect not only the cellular origin but also the stimulus that triggered their biogenesis and secretion. This chapter presents an overview of the biology of EC-EVs and summarizes key findings regarding their characteristics, components, and functions. The role of EC-EVs is specifically delineated in pulmonary diseases characterized by endothelial dysfunction, including pulmonary hypertension, acute respiratory distress syndrome and associated conditions, chronic obstructive pulmonary disease, and obstructive sleep apnea.

Keywords: ARDS; Exosome; Extracellular vesicle; Lung injury; Microparticle; Microvesicle; Pulmonary endothelium; Pulmonary vascular disease.

Figure 1.. Schematic representation of endothelial cell-derived extracellular vesicles (EC-EVs).

EV main categories, microvesicles and exosomes, carry common components (A) but also are enriched in specific molecules (B and C). EC markers that identify EVs of endothelial origin include CD62E, CD31, CD144, CD105, CD54, and vWF. Abbreviations: CD62E; E-selectin, CD31; PECAM-1, CD144; VE-cadherin, CD105; endoglin, CD54; ICAM-1, vWF; von Willebrand factor, ACE; angiotensin converting enzyme, TF; tissue factor, PS; phosphatidylserine, TSG101; tumor susceptibility gene 101 protein, CD9, CD63, CD81, CD82; tetraspanins.

Figure 2.. Endothelial EV-Cell interactions in homeostasis and lung disease.

(A) Vascular or progenitor endothelial cells secrete EVs spontaneously into the circulating blood where they contribute to primary homeostatic functions and repair by promoting angiogenesis, proliferation, and other anti-inflammatory effects. (B) Increased numbers of microvesicles and exosomes are released from EC after stimulation with lung disease-relevant stimuli such as hypoxia, mechanical stretch, bacterial toxins (e.g. LPS), inflammatory cytokines (e.g. TNF-α) and other endogenous mediators (e.g. thrombin), or toxic substances (e.g. cigarette smoke). Upon their release, EC-EVs interact with the vascular endothelium (1) or modulate the activities of circulating blood cells (2) to promote lung damage by inducing endothelial dysfunction, pro-inflammatory signaling, coagulation, etc. EVs can also be released from the basolateral EC surface or escape the circulation after EC barrier disruption and target other lung cells such as smooth muscle cells and macrophages (3). Abbreviations: PH; Pulmonary hypertension, ARDS; Acute respiratory distress syndrome, COPD; chronic obstructive pulmonary disease, OSA; obstructive sleep apnea.