Circulating Extracellular Vesicles in Normotension Restrain Vasodilation in Resistance Arteries

Abstract

Extracellular vesicles (EVs) have been described as novel biomarkers and bioactivators in vascular dysfunction in hypertension. However, the mechanism(s) by which EVs affect vascular function is unknown. To examine the effects of EVs on endothelial-dependent vasodilation (acetylcholine), we isolated circulating EVs from platelet-poor plasma using a low centrifugation speed (17 000 g ) and mesenteric resistance arteries from 12-week-old normotensive WKYs (Wistar-Kyoto rats) and SHRs (spontaneously hypertensive rats). Arteries were cannulated on a pressure myograph, and EVs were added to the vessel lumen and circulating bath. We found that circulating EVs from normotensive WKY reduced vasodilation of normotensive WKY arteries but had no effect on hypertensive SHR arteries. In contrast, EVs from hypertensive SHR failed to reduce vasodilation of arteries from both WKY and SHR. The restraining effect on vasodilation by EVs from normotensive WKY may be mediated by inhibition of eNOS (endothelial NO synthase), as addition of L-nitro-arginine methyl ester did not provide any additive effect. Moreover, circulating EVs from normotensive 6-week-old SHR—an age where SHRs have not yet developed hypertension—had similar restraining effect on vasodilation. In addition, delipidation of EVs did not alter the restraining effect of EVs from WKY but did restore the restraining effect of EVs from SHR. Finally, EVs from normotensive humans also restrained vasodilation of normotensive mouse arteries—an effect not observed in EVs from hypertensive humans. Taken together, our data support a vasoactive role of EVs that is altered in hypertension.

Importance of extracellular vesicles in hypertension

“…observed that circulating EVs from WKY rats reduced vasodilation of isolated WKY mesenteric arteries but had no effect on SHR mesenteric arteries. However, EVs from hypertensive SHRs failed to reduce vasodilation from both WKY and SHRs 67. These data support the idea that a blood pressure regulating effect of EVs changes after the development of hypertension.…”

“…It should be noted that the therapeutic potential of EVs in hypertension is still in its early phase. An ex vivo study demonstrated plasma-poor circulating EVs from WKY and SHRs can differentially modulate vasoreactivity of isolated mesenteric vessels 67. There is one animal study that demonstrated the potential of plasma EVs to regulate systemic blood pressure with beneficial effect on end-organ damage in hypertension 65.…”

T cell-derived extracellular vesicles are elevated in essential HTN

“…However, similarly to Zu et al, using the SHR model of essential HTN (5), we recently reported that leukocyte-derived EVs (CD31 + and CD45 + ) were significantly elevated in SHRs at 12 wk of age compared with agematched normotensive Wistar-Kyoto rats. In this model of essential HTN, we also observed that circulating levels of EVs correlated with blood pressure severity (5).…”

“…EVs derived from T cell culture have been shown to reduce endothelium-dependent vasodilation in resistance arteries from mice, likely via a NO-dependent mechanism (14). Our own group found that the levels of leukocyte-derived EVs, and not endothelium-derived EVs, are elevated in spontaneously hypertensive rats (SHRs) and correlate well with the severity of HTN (5). Therefore, we aimed to understand if specific subtypes of leukocyte/immune cell-derived EVs are altered in essential HTN using an in vivo model of ANG II-induced HTN.…”

In sickness and in health: The functional role of extracellular vesicles in physiology and pathology in vivo

“…As discussed in Part I, EVs have been shown to modulate blood pressure, which may be considered homeostatic, although they may also have downstream pathogenic consequences. For example, work in rats has identified that circulating EVs are capable of restraining vasodilation (Good et al., 2020 ; Otani et al., 2018 ), and that this may play an important role in hypertension. Indeed, increased endothelial EVs have been reported in the plasma (Preston et al., 2003 ) and urine (Sun et al., 2018 ) of hypertensive patients.…”