Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm
Johanne Poisson, … , Chantal M. Boulanger, Pierre-Emmanuel Rautou
Johanne Poisson, … , Chantal M. Boulanger, Pierre-Emmanuel Rautou
Published February 11, 2020
Citation Information: J Clin Invest. 2020;130(5):2630-2643. https://doi.org/10.1172/JCI124566.
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Research Article Cardiology Hematology

Erythrocyte-derived microvesicles induce arterial spasms in JAK2V617F myeloproliferative neoplasm

Abstract

Arterial cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms (MPNs). However, their mechanisms are poorly understood. The high prevalence of myocardial infarction without significant coronary stenosis or atherosclerosis in patients with MPNs suggests that vascular function is altered. The consequences of JAK2V617F mutation on vascular reactivity are unknown. We observe here increased responses to vasoconstrictors in arteries from Jak2V617F mice resulting from a disturbed endothelial NO pathway and increased endothelial oxidative stress. This response was reproduced in WT mice by circulating microvesicles isolated from patients carrying JAK2V617F and by erythrocyte-derived microvesicles from transgenic mice. Microvesicles of other cellular origins had no effect. This effect was observed ex vivo on isolated aortas, but also in vivo on femoral arteries. Proteomic analysis of microvesicles derived from JAK2V617F erythrocytes identified increased expression of myeloperoxidase as the likely mechanism accounting for their effect. Myeloperoxidase inhibition in microvesicles derived from JAK2V617F erythrocytes suppressed their effect on oxidative stress. Antioxidants such as simvastatin and N-acetyl cysteine improved arterial dysfunction in Jak2V617F mice. In conclusion, JAK2V617F MPNs are characterized by exacerbated vasoconstrictor responses resulting from increased endothelial oxidative stress caused by circulating erythrocyte-derived microvesicles. Simvastatin appears to be a promising therapeutic strategy in this setting.

Authors

Johanne Poisson, Marion Tanguy, Hortense Davy, Fatoumata Camara, Marie-Belle El Mdawar, Marouane Kheloufi, Tracy Dagher, Cécile Devue, Juliette Lasselin, Aurélie Plessier, Salma Merchant, Olivier Blanc-Brude, Michèle Souyri, Nathalie Mougenot, Florent Dingli, Damarys Loew, Stephane N. Hatem, Chloé James, Jean-Luc Villeval, Chantal M. Boulanger, Pierre-Emmanuel Rautou

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Figure 4

Disturbed endothelial NO pathway and increased oxidative stress status.

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Disturbed endothelial NO pathway and increased oxidative stress status. ...
Cumulative dose-response curve of aortas from Jak2V617F HC-EC mice and littermate controls (Jak2WT) to acetylcholine (n = 11 and n = 11, respectively) (A) and to SNAP (n = 5 and n = 6, respectively) (C), and to phenylephrine after l-NAME incubation (n = 11 and n = 7, respectively) (E). Diameter change of femoral arteries after injection of acetylcholine (10–2 mol/L) (Jak2WT, n = 8; Jak2V617F HC-EC, n = 8) (B) and SNAP (10–3 mol/L) (Jak2WT, n = 4; Jak2V617F HC-EC, n = 4) (D). Quantification of ROS generation (red surface) per endothelial cell in control mice (Jak2WT) versus Jak2V617F HC-EC mice (F); control mice (Jak2WT) versus Jak2V617F EC mice (H); control mice injected with microvesicles derived from control (Jak2WT RBC MVs, n = 6) or JAK2V617F erythrocytes (Jak2V617F RBC MVs, n = 6) (J). Representative images of en face endothelial staining with CellROX (red fluorogenic probes for ROS generation) and DAPI (nuclei in blue) of aortas (G, I, and K). Scale bars: 10 μm. (L) Cumulative dose-response curve to phenylephrine of aortas from Jak2V617F HC-EC mice treated with vehicle (n = 5) and with NAC (n = 7). *P < 0.05, **P < 0.01, ***P < 0.001. Quantitative data are expressed as median with IQR and compared using the Mann-Whitney U test, and cumulative dose-response curves are expressed as mean with SEM and compared using ANOVA for repeated measures.