Hypoxia and extracellular vesicles: A review on methods, vesicular cargo and functions

Abstract

Hypoxia is an essential hallmark of several serious diseases such as cardiovascular and metabolic disorders and cancer. A decline in the tissue oxygen level induces hypoxic responses in cells which strive to adapt to the changed conditions. A failure to adapt to prolonged or severe hypoxia can trigger cell death. While some cell types, such as neurons, are highly vulnerable to hypoxia, cancer cells take advantage of a hypoxic environment to undergo tumour growth, angiogenesis and metastasis. Hypoxia‐induced processes trigger complex intercellular communication and there are now indications that extracellular vesicles (EVs) play a fundamental role in these processes. Recent developments in EV isolation and characterization methodology have increased the awareness of the importance of EV purity in functional and cargo studies. Cell death, a hallmark of severe hypoxia, is a known source of intracellular contaminants in isolated EVs. In this review, methodological aspects of studies investigating hypoxia‐induced EVs are critically evaluated. Key concerns and gaps in the current knowledge are highlighted and future directions for studies are set. To accelerate and advance research, an in‐depth analysis of the functions and cargo of hypoxic EVs, compared to normoxic EVs, is provided with the focus on the altered microRNA contents of the EVs.

Extracellular Vesicles under Oxidative Stress Conditions: Biological Properties and Physiological Roles

“…The biogenesis and release of EVs has been demonstrated to be increased in different stress situations. These include hypoxia [ 32 ] and conditions such as senescence [ 33 , 34 ] or oncogene activation [ 35 ], which are known to affect the activation status of p53 [ 36 ]. The lysosomal status was also suggested to have an impact on the release of EVs, as well as oxidative stress [ 37 ].…”

Cell-Selective Altered Cargo Properties of Extracellular Vesicles Following In Vitro Exposures to Intermittent Hypoxia

“…Endothelial cells play a key role in maintaining constant vascular tension, and vascular endothelial dysfunction, which is characterized by imbalanced vasoconstrictive and vasodilatory molecules, is the earliest sign of a vascular lesion preceding the occurrence of clinically obvious cardiovascular complications in OSA [ 17 , 19 , 97 , 98 ]. Hypoxia can also trigger complex intercellular communication, may aggravate endothelial dysfunction and destruction in early pre-atherosclerosis, and induce vascularization in cancer tissue and a progression of the disease [ 99 , 100 , 101 ]. In addition, hypoxic preconditioning for 24 h of mesenchymal stem cells improves their efficacy in the treatment of cardiovascular diseases [ 102 ].…”

The Current Status of Mesenchymal Stromal Cells: Controversies, Unresolved Issues and Some Promising Solutions to Improve Their Therapeutic Efficacy

“…The term “secretome” includes diverse soluble molecules, such as growth factors, cytokines, immunomodulatory molecules and the named EVs ( Kusuma et al, 2017 ). EVs are a heterogeneous population of lipid-bilayer vesicles that contain biologically active biomolecules such as lipids, proteins, single-stranded DNA and different types of RNAs ( Bister et al, 2020 ; Watanabe et al, 2021 ). They include small exosomes (40–120 nm) originated from multivesicular bodies of the endosomal compartment that are secreted by exocytosis, and larger microvesicles (200–1,000 nm) that bud directly from the plasma membrane ( Kusuma et al, 2017 ).…”