患有 JAK2V617F 阳性骨髓增生性肿瘤 (MPN) 和具有不确定潜力的克隆造血的患者面临显着升高的心血管疾病风险。在许多 MPN 患者中检测到携带 JAK2V617F 突变的内皮细胞。在这项研究中，我们研究了 MPN 患者心血管并发症高发的分子基础。我们使用转基因小鼠模型和 MPN 患者衍生的诱导多能干细胞系研究了内皮 JAK2V617F 突变对心血管疾病发展的影响。研究表明，JAK2V617F突变内皮细胞在应激下会促进心血管疾病，这与内皮间质转化和内皮功能障碍有关。重要的是，我们发现抑制内皮TPO（血小板生成素）受体MPL可以抑制JAK2V617F诱导的内皮向间质转化，并预防突变内皮细胞引起的心血管功能障碍。值得注意的是，内皮MPL受体对于血细胞计数和心脏功能的正常生理调节并不是必需的。JAK2V617F突变内皮细胞在JAK2V617F阳性MPN的心血管疾病的发展中发挥着关键作用，内皮MPL可能是一种有前途的治疗方法预防或改善这些患者心血管并发症的目标。

Patients with JAK2V617F-positive myeloproliferative neoplasms (MPNs) and clonal hematopoiesis of indeterminate potential face a significantly elevated risk of cardiovascular diseases. Endothelial cells carrying the JAK2V617F mutation have been detected in many patients with MPN. In this study, we investigated the molecular basis for the high incidence of cardiovascular complications in patients with MPN.We investigated the impact of endothelial JAK2V617F mutation on cardiovascular disease development using both transgenic murine models and MPN patient-derived induced pluripotent stem cell lines.Our investigations revealed that JAK2V617F mutant endothelial cells promote cardiovascular diseases under stress, which is associated with endothelial-to-mesenchymal transition and endothelial dysfunction. Importantly, we discovered that inhibiting the endothelial TPO (thrombopoietin) receptor MPL suppressed JAK2V617F-induced endothelial-to-mesenchymal transition and prevented cardiovascular dysfunction caused by mutant endothelial cells. Notably, the endothelial MPL receptor is not essential for the normal physiological regulation of blood cell counts and cardiac function.JAK2V617F mutant endothelial cells play a critical role in the development of cardiovascular diseases in JAK2V617F-positive MPNs, and endothelial MPL could be a promising therapeutic target for preventing or ameliorating cardiovascular complications in these patients.