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Extracellular Vesicles as Biomarkers and Biovectors in Primary Aldosteronism.

All cell types are capable of generating small heterogeneous vesicles called extracellular vesicles (EVs). EVs are released from activated or stressed parent cells into the extracellular space, such as plasma, cerebrovascular fluid, breast milk, urine, and saliva, and reflect the activation status and phenotype of the parent cell from which they were derived. Based on biogenesis, content, and size, EVs are classified as exosomes (40– 100 nm), microparticles (also termed microvesicles; 100–1000 nm), and apoptotic bodies (1–5 μm). EVs were initially identified as cellular dust and considered to be cell debris. However, there is now good evidence in experimental and clinical studies demonstrating that EVs are biomarkers of disease, including cancer, metabolic disorders, and cardiovascular diseases. Moreover, it has become increasingly apparent that they are biologically active and are important signaling vehicles and regulators of local and distant cell-cell communication. EVs act as biovectors carrying cargo, such as proteins, lipids, receptors, RNA, microRNA, and enzymes, which are derived primarily from parent cells. They communicate with target cells, through diverse mechanisms, including release of cargo into the extracellular space, cell membrane binding, cell membrane fusion, and endocytosis by target cells. Through these interactions and transfer of cargo, EVs influence the function of other cells. For example, neutrophil-derived microvesicles carry cytokines, which function as proinflammatory mediators. Cancer cell– derived microparticles release metalloproteases and promote tumor invasion and metastases and platelet-derived microparticles transfer microRNA-142 into endothelial cells causing endothelial dysfunction. As biomarkers in cardiovascular disease, platelet microparticles correlate with the development of hypertension, levels of endothelial cell-derived microparticles associate with type 2 diabetes mellitus, and hypertension and circulating exosomes associate with myocardial infarction, cardiomyopathies, and pulmonary hypertension. In hypertension, EV levels also correlate with arterial stiffness, endothelial dysfunction, and impaired vasoreactivity and accordingly have been suggested to reflect underlying vascular status. Beyond their role as vascular biomarkers, EVs directly regulate endothelial and vascular smooth muscle cell function by influencing production of NO and reactive oxygen species, proinflammatory signaling, apoptosis, and senescence. These processes have been implicated in various experimental models of hypertension, including Ang II (angiotensin II)-infused, Spontaneously Hypertensive Rats Stroke Prone, deoxycorticosterone acetate-salt, Spontaneously Hypertensive Rats and in patients with essential hypertension. In the current issue of the journal, Burrello et al advance the field by demonstrating that the number of EVs derived mainly from leucocytes and endothelial cells are significantly increased in patients with primary aldosteronism when compared with individuals with essential hypertension and those with normal blood pressure, effects that were normalized postadrenelectomy. Moreover, findings from this study showed a strong correlation between serum aldosterone levels and number of circulating EVs. Similar findings have been observed in experimental models of aldosterone-salt-induced hypertension. Patients with primary aldosteronism have a higher prevalence of target organ damage and cardiovascular events compared with patients with essential hypertension, and endothelial dysfunction is associated, at least partially, with the increased cardiovascular risk observed in these patients. Therefore, considering EVs as surrogate markers of endothelial dysfunction and vascular injury, these data support the notion that the greater the magnitude of endothelial dysfunction in primary aldosteronism, the higher the levels of circulating EVs. Renal-derived urinary exosomes have also been shown to be increased in patients with hyperaldosteronism and have been suggested to be markers of aldosteroneinduced renal disease. Despite the accumulating evidence showing a relationship between hyperaldosteronism and EV formation, it remains unclear whether increased production is a primary effect of high levels of aldosterone or whether increased generation is secondary to aldosterone-induced vascular injury and hypertension. Also, it may be possible that changes in plasma K due to hyperaldosteronism influence EV production, as previously suggested. Shear stress and elevated blood pressure probably contribute, at least in part to increased circulating EVs, but it may be possible that aldosterone itself can stimulate generation of EVs from various cell types. We previously demonstrated that generation of endothelial cell–derived microparticles depends on mechanisms involving Rho kinase, cholesterol-rich microdomains and cytoskeletal organization, This paper was sent to Morris Brown, Guest Editor, for review by expert referees, editorial decision, and final disposition. The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, United Kingdom. Correspondence to Karla Bianca Neves, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Pl, Glasgow G12 8TA, United Kingdom. Email Karla.Neves@glasgow.ac.uk Extracellular Vesicles as Biomarkers and Biovectors in Primary Aldosteronism