Platelet-Derived Microvesicles in Cardiovascular Diseases

Abstract

Microvesicles (MVs) circulating in the blood are small vesicles (100-1,000 nm in diameter) derived from membrane blebs of cells such as activated platelets, endothelial cells, and leukocytes. A growing body of evidence now supports the concept that platelet-derived microvesicles (PMVs), the most abundant MVs in the circulation, are important regulators of hemostasis, inflammation, and angiogenesis. Compared with healthy individuals, a large increase of circulating PMVs has been observed, particularly in patients with cardiovascular diseases. As observed in MVs from other parent cells, PMVs exert their biological effects in multiple ways, such as triggering various intercellular signaling cascades and by participating in transcellular communication by the transfer of their "cargo" of cytoplasmic components and surface receptors to other cell types. This review describes our current understanding of the potential role of PMVs in mediating hemostasis, inflammation, and angiogenesis and their consequences on the pathogenesis of cardiovascular diseases, such as atherosclerosis, myocardial infarction, and venous thrombosis. Furthermore, new developments of the therapeutic potential of PMVs for the treatment of cardiovascular diseases will be discussed.

Keywords: angiogenesis; cardiovascular disease; hemostasis; inflammation; microvesicles; platelet-derived microvesicles; therapeutic potential.

Figure 1

PMV formation and characteristics. Upon cellular activation, the elevation of intracellular calcium inhibits flippase, while activating floppase and scramblase (TMEM16F), mediating the externalization of negatively charged PS (indicated as purple phospholipid). Furthermore, increased intracellular calcium leads to reorganization of the cytoskeleton by activating calpain, thereby cleaving PMVs and releasing them into the circulation. The size, physical characteristics, and cargo of PMVs depend on the environment and agonist(s) causing PMV generation. PMVs share many surface proteins with platelets such as integrins, selectins, adhesion receptors, coagulation factors, and other platelet-derived proteins. PMVs are packed with proteins including growth factors, cytokines/chemokines, and apoptotic proteins. PMVs also carry nucleic acids (mRNA, miRNA, and RNA) and mitochondria. PS, phosphatidylserine; GP, glycoprotein; vWF, von Willebrand factor; RNA, ribonucleic acid; mRNA, messenger RNA; miRNA, microRNA; PMV, platelet-derived microvesicle.

Figure 2

Platelet-derived microvesicles (PMVs) as regulators of hemostasis and contributors to cardiovascular diseases. The physical characteristics of the cell membrane and biological cargo define the biological role of PMVs. PMVs bind natural anticoagulants thereby preventing coagulation. PMVs can also inhibit cytokine production leading to a reduction of vascular inflammation. In addition, PMVs can enhance the vasogenerative capacity of cells, thus highlighting their role in wound healing. While PMVs play a major role in regulating hemostasis, excessive numbers of PMVs can also contribute to cardiovascular diseases. The presence of phosphatidylserine and tissue factor in PMVs can induce procoagulant enzyme–cofactor complexes that favor thrombosis. PMVs can also induce cytokine production, bind protein C-reactive protein (pCRP), and convert it to monomer of C-reactive protein (mCRP), thereby promoting inflammatory responses. The activation of smooth muscle cells, endothelial cells, and leukocytes by PMVs as well as growth factors encapsulated within PMVs can stimulate angiogenesis. Therefore, PMVs may stimulate or dampen coagulation, inflammation, and angiogenesis and may thereby contribute to cardiovascular diseases.