**3.1 Platelet-derived EVs**

EVs from activated platelets can have different effects on endothelial cells, monocytes and other platelets (**Figure 2A**). Namely, increased levels of intracellular adhesion molecule-1 (ICAM-1), a well-known activator of endothelium was observed on endothelial cells upon stimulation with platelet EVs [42, 43], an effect later ascribed to miR-320b transfer [42]. Increased expression of lymphocyte function-associated antigen-1 LFA-1 (CD11a/CD18) and macrophage antigen-1 Mac-1 (CD11b/CD18); both important in mediating monocyte-endothelium interactions, were observed on monocytes upon stimulation with platelet EVs. These effects are induced by the transfer of arachidonic acid from platelet EVs and appear to be dependent on the activation of protein kinase C [44]. Platelet EVs therefore significantly modulate adhesion of monocytes to endothelial cells. It has also been shown that platelet EVs increase the deposition of platelets on damaged arteries and increase platelet aggregation and adhesion to collagen [45]. By influencing

#### **Figure 2.**

*Activation of platelets, monocytes and endothelial cells by EVs deriving from different cells. Schematic representation of the potential in vitro mechanisms focusing on vascular function, inflammation and thrombosis. (A) Platelet EVs can stimulate endothelial cells and monocytes via direct interaction or cargo delivery (miR and lipids). Furthermore, platelets EVs can also act via a feedback loop causing platelet aggregation and activation. Platelet EVs induce endothelial cell activation, proliferation and apoptosis by the transfer or miR-223 and miR-142-3p while ICAM-1 expression is induced by the delivery of miR-320b. Increased adhesion between endothelial cells and monocytes as well as between leukocytes in mediated by platelet EVs. (B) EVs released form endothelial cells were found to have a procoagulant profile expressing vWF, TF, PAI-1, PS as well as increased adhesive properties expressing VCAM-1, ICAM-1, E-selectin, and α-integrin. Endothelial EVs promote procoagulant profile of monocytes by induction of the TF expression on these cells. Endothelial EVs induce endothelial dysfunction by attenuating the production of nitric oxide from endothelial cells (C) Monocytes release procoagulant EVs that carry TF and PS. Furthermore, monocyte EVs interact with endothelial cells causing increased expression of adhesion molecules (ICAM-1, VCAM-1 and E-selectin), increased inflammation and procoagulant profile by reducing the expression of anticoagulant molecules (TFPI and Trombomodulin). Monocyte EVs transfer miR cargo (miR125a-5p, miR-222, miR-146a, miR-146b, miR-155) and induce inflammation in endothelial cells. CCL2, C-C motif chemokine ligand 2; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; LFA1; lymphocyte function-associated antigen 1; Mac-1, Macrophage antigen-1; mIR; micro RNA; MyD88, myeloid differentiation primary response gene 88; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; PS, phosphatidylserine; TF, tissue factor; TLR4, tool like receptor 4; VCAM-1, vascular cell adhesion molecule 1; vWF, von Willebrand factor. Created with BioRender.com.*

cell adhesiveness, EVs also modulate interactions between leukocytes. Platelet EVs use P-selectin to bridge leukocytes, increase leukocyte-leukocyte interactions and enhance leukocyte accumulation on a P-selectin surface [46, 47]. Platelet EVs can therefore contribute to increased adhesion and aggregation of platelets and leukocytes on blood vessel walls during pathology. In addition, platelet EVs influence the production of cytokines (IL-1β, IL-6, IL-8) [43] and the transfer of miRNA (miRs 142-3p and 223), affecting the activation, proliferation and apoptosis of endothelial cells [48, 49]. In addition, platelet activation by the transfer of arachidonic acid from platelet EVs to other platelets, was observed [50]. Importantly, the role of platelet EVs in hemostasis is not entirely clear, as there is evidence that these EVs can also have anticoagulant effects [51, 52]. Further research is needed to determine, which key stimuli are responsible for determining the final effect of platelet EVs.

### **3.2 Endothelial-derived EVs**

Endothelial cell activation and damage play an important role in vascular pathologies, with endothelial EVs being proposed as one of the causative agents in vascular pathologies (**Figure 2B**). Many proinflammatory factors (e.g. TNF-α, lipopolysaccharide, C-reactive protein and reactive oxygen species) and coagulation stimuli (thrombin, plasminogen activator inhibitor-1 (PAI-1)) can increase the

#### *Extracellular Vesicles: Intercellular Communication Mediators in Antiphospholipid Syndrome DOI: http://dx.doi.org/10.5772/intechopen.97412*

levels of endothelial EVs. These vesicles carry adhesion molecules; ICAM-1, vascular cell adhesion protein 1 (VCAM-1), E-selectin, VE-cadherin, α-integrin, growth factors; endoglin, CD146, vascular endothelial growth factor (VEGF) receptor and molecules involved in coagulation, such as von Willebrand factor (vWF), TF, PAI-1 [53–55]. The expression of anionic phospholipids; such as PS, together with coagulation molecules, contribute to their procoagulant role. In addition, endothelial EVs may interact with other cells such as monocytes and induce the expression of TF on these cells [56]. Endothelial EVs induce endothelial dysfunction by attenuating the production of nitric oxide from endothelial cells [57]. Conversely, endothelial EVs may also have anticoagulant and antiinflammatory potential [38]. Although they exert different effects that are mostly dependent on the environment they originate from, endothelial EVs are generally believed to impair vascular function [58].
