Crucial role of hematopoietic JAK2 V617F in the development of aortic aneurysms.

Abstract

JAK2 V617F is the most frequent driver mutation in myeloproliferative neoplasms (MPN) and is associated with vascular complications. However, the impact of hematopoietic JAK2 V617F on aortic aneurysms (AA) remains unknown. Our cross-sectional study indicated that nine (23%) of 39 MPN patients with JAK2 V617F exhibited the presence of AA. In order to clarify whether the hematopoietic JAK2 V617F contributes to the AA, we applied bone marrow transplantation (BMT) with the donor cells from Jak2 V617F transgenic (JAK2V617F) mice or control wild-type (WT) mice into lethally irradiated apolipoprotein E-deficient mice. Five weeks after BMT, the JAK2V617F-BMT mice and WT-BMT mice were subjected to continuous angiotensin II infusion to induce AA formation. Four weeks after angiotensin II infusion, the abdominal aorta diameter in the JAK2V617F-BMT mice was significantly enlarged compared to that in the WT-BMT mice. Additionally, the abdominal AA-free survival rate was significantly lower in the JAK2V617F-BMT mice. Hematopoietic JAK2 V617F accelerated aortic elastic lamina degradation as well as activation of matrix metalloproteinase (MMP)-2 and MMP-9 in the abdominal aorta. The numbers of infiltrated macrophages were significantly upregulated in the abdominal aorta of the JAK2V617F-BMT mice accompanied by STAT3 phosphorylation. The accumulation of BM-derived hematopoietic cells carrying JAK2 V617F in the abdominal aorta was confirmed by use of the reporter green fluorescent proteintransgene. BM-derived macrophages carrying JAK2 V617F showed increases in mRNA expression levels of Mmp2, Mmp9, and Mmp13. Ruxolitinib decreased the abdominal aorta diameter and the incidence of abdominal AA in the JAK2V617F-BMT mice. Our findings provide a novel feature of vascular complications of AA in MPN with JAK2 V617F.