Importance of extracellular vesicles in hypertension

Abstract

Hypertension affects approximately 1.13 billion adults worldwide and is the leading global risk factor for cardiovascular, cerebrovascular, and kidney diseases. There is emerging evidence that extracellular vesicles participate in the development and progression of hypertension. Extracellular vesicles are membrane-enclosed structures released from nearly all types of eukaryotic cells. During their formation, extracellular vesicles incorporate various parent cell components, including proteins, lipids, and nucleic acids that can be transferred to recipient cells. Extracellular vesicles mediate cell-to-cell communication in a variety of physiological and pathophysiological processes. Therefore, studying the role of circulating and urinary extracellular vesicles in hypertension has the potential to identify novel noninvasive biomarkers and therapeutic targets of different hypertension phenotypes. This review discusses the classification and biogenesis of three EV subcategories (exosomes, microvesicles, and apoptotic bodies) and provides a summary of recent discoveries in the potential impact of extracellular vesicles on hypertension with a specific focus on their role in the blood pressure regulation by organs-artery and kidney, as well as renin-angiotensin-system.

Keywords: Hypertension; RAS; endothelium; extracellular vesicles; sodium transporter; vascular smooth muscle cells.

Figure 1.

EV biogenesis and interaction with recipient cells. (a) Exosome formation starts with inward budding of the plasma membrane and transfer of early endosomes. During early endosome invagination, cytosolic proteins, RNAs, enzyme, antigen, lipids, and other components are incorporated into the intraluminal vesicles. When multivesicular bodies fuse with the lysosome, the protein contents get degraded. When multivesicular bodies fuse with the plasma membrane, exosomes are released. (b) Microvesicles: external stress, e.g. oxidative stress, hypoxia, increases the cytosolic concentration of calcium to induce specific membrane changes and loosen the cytoskeleton, which leads to outward protrusion of the plasma membrane and the formation of microvesicles. (c) Apoptotic bodies: These are released during the late stage of programmed cell death. They contain several intracellular fragments and damaged cellular organelles, as well as other molecules similar to those inside microvesicles. EVs mediate cell-to-cell communication through different mechanisms: (1) ligand-receptor interaction causes the accumulation of EV contents, e.g. inflammatory cytokines, angiogenic factors, growth factors, and extracellular matrix proteins. (2) EV-plasma membrane fusion causes the release of EV content into the recipient cell cytoplasm. 3) Receptor cell internalization causes the endocytosis of EVs to deliver their contents. EVs: extracellular vesicles.

Figure 2.

Role of EVs in the development and progression of hypertension. Risk factors for hypertension-induced events cause the release of systemic and urinary EVs from various cells. EV activation contributes to the pathogenesis of hypertension and hypertension-induced events, such as vascular and kidney dysfunction, including impaired endothelial function, VSMC proliferation and migration, altered NHE3, NCC, ENaC activity, and maladaptive of RAS. These processes collectively contribute to the development and progression of hypertension. EVs: extracellular vesicles; VSMCs: vascular smooth muscle cells; NHE3: sodium/hydrogen exchanger type 3; NCC: sodium chloride cotransporter; ENaC: epithelial sodium channel; RAS: renin-angiotensin-system.