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 1

JAK2V617F in hematopoietic and endothelial cells increases arterial contraction in an endothelium-dependent manner.

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JAK2V617F in hematopoietic and endothelial cells increases arterial cont...
(A) Representative image of the spleen. Hemoglobin level (B), platelet count (C), and WBC count (D) of 8 -to 12-week-old control mice (Jak2WT, n = 13) and Jak2V617F Flex/WT VE-cadherin-Cre mice (Jak2V617F HC-EC, n = 13). Cumulative dose-response curves to phenylephrine (Jak2WT, n = 13; Jak2V617F HC-EC, n = 13) (E) and to angiotensin II (Jak2WT, n = 3; Jak2V617F HC-EC, n = 4) (G), and contraction response to potassium chloride (80 mmol/L) (Jak2WT, n = 13; Jak2V617F HC-EC, n = 13) of aortas with endothelium (F). (H) Cumulative dose-response curves to phenylephrine of aortas without endothelium (Jak2WT, n = 6; Jak2V617F HC-EC, n = 6). (I) Diameter change of femoral artery after phenylephrine injection (10–3 mol/L) (Jak2WT, n = 8; Jak2V617F HC-EC, n = 8). Electrocardiogram recording before and after intravenous phenylephrine (Phe) injection (3 mg/kg; Jak2WT, n = 13; Jak2V617F HC-EC, n = 6) (J), with representative images of the changes observed in 5 of 6 Jak2V617F HC-EC versus 4 of 13 Jak2WT mice (P = 0.057) (K). Quantitative data are expressed as median with IQR, and cumulative dose-response curves are expressed as mean with SEM. *P < 0.05, ***P < 0.001. Cumulative dose-response curves and electrocardiogram recordings were compared using ANOVA for repeated measures, and other data were compared using the Mann-Whitney U test. All tests were 2 sided.