Circulating membrane-derived microvesicles in redox biology

Abstract

Microparticles or microvesicles (MVs) are subcellular membrane blebs shed from all cells in response to various stimuli. MVs carry a battery of signaling molecules, many of them related to redox-regulated processes. The role of MVs, either as a cause or as a result of cellular redox signaling, has been increasingly recognized over the past decade. This is in part due to advances in flow cytometry and its detection of MVs. Notably, recent studies have shown that circulating MVs from platelets and endothelial cells drive reactive species-dependent angiogenesis; circulating MVs in cancer alter the microenvironment and enhance invasion through horizontal transfer of mutated proteins and nucleic acids and harbor redox-regulated matrix metalloproteinases and procoagulative surface molecules; and circulating MVs from red blood cells and other cells modulate cell-cell interactions through scavenging or production of nitric oxide and other free radicals. Although our recognition of MVs in redox-related processes is growing, especially in the vascular biology field, much remains unknown regarding the various biologic and pathologic functions of MVs. Like reactive oxygen and nitrogen species, MVs were originally believed to have a solely pathological role in biology. And like our understanding of reactive species, it is now clear that MVs also play an important role in normal growth, development, and homeostasis. We are just beginning to understand how MVs are involved in various biological processes-developmental, homeostatic, and pathological-and the role of MVs in redox signaling is a rich and exciting area of investigation.

Keywords: Free radicals; Microparticles; Microvesicles; Pathology; Phospholipids; Redox signaling.

Copyright © 2014 Elsevier Inc. All rights reserved.

Figures

Figure 1. Membrane Vesicles

Schematic depicting the difference between exosomes (smallest), microparticles/microvesicles, and apoptotic bodies (largest).

Figure 2. Web of Science literature search

Results of a search for circulating, vascular, or circulation and MVs. Left, top) publications per year and left, bottom) citations per year. Right) Modified pie chart showing studies with MV types mentioned. Connecting lines are weighted to the number of publications listing multiple MV types.

Figure 3. MVs in healthy individuals

Results from searching for “circulating microparticles” and “healthy controls”. The percent of circulating MVs by type in controls is shown. Points are sized relative to the number of control plasmas examined. Insert) MVs per microliter. The patient demographics, methods for drawing, clarification to remove cells, centrifugation to remove platelets, labeling, and detection all differed among the studies, highlighting the variability of the results across the studies. Taken from refs. [–41]

Figure 4. Centrifugation and resulting MV sizing

Variability seen in characterization of vesicles may in part be explained by the method used to isolate them. The reported maximum centrifugation speed used to remove parent cells was compared against the maximum size or diameter of the resulting RBC-derived MVs. The trend fit an exponential decay curve (R2=0.83). Taken from > [,,,–197] (and Larson et al., manuscript in preparation for “1g” sedimentation).

Figure 5. Mechanisms of MV formation

Shown are general mechanisms underlying cellular MV formation, including electrolyte/hydration shift, membrane (bilayer and structural support) oxidative damage, physical stress, pharmacological signaling, and mitochondrial and apoptotic signaling pathways.

Figure 6. Platelet MVs participate in redox processes

Platelet activation results in MV formation. Platelet MVs act upon endothelial cells, WBCs, cancer cells, and other platelets via the various known redox effectors listed in the inset. These MV-cell interactions cause enhanced adhesion and cellular activation, which result in ROS production, intracellular signaling, apoptosis, and angiogenesis to name a few redox-regulated processes.

Figure 7. Endothelial MVs mediate oxidative stress and vascular injury

Various redox-regulated effectors, proteins and pathways result in endothelial cell vesicluation, with the MV cargo varying depending on the stimulus. Endothelial MVs then influence vasculature cells by enhancing adhesion, triggering hemostasis, orchestrating cell activation or differentiation, and enhancing or inducing apoptosis by various beneficial or damaging mediators as shown in the inset. TF, Tissue Factor; CRP, C-Reactive Protein.

Figure 8. RBC MV formation and function relating to oxidative stress

RBCs experiencing overwhelming oxidative stress/damage shed MVs with hemoglobin (Hb). These RBC MVs bear Hb capable of scavenging nitric oxide (NO) and pro-coagulative phospholipids, leading to a pro-thrombotic state.