Am J Pathol. 2026 Aug 7:S0002-9440(26)00227-0. doi: 10.1016/j.ajpath.2026.07.005. Online ahead of print.
ABSTRACT
Cardiovascular disease (CVD) is a major complication of JAK2V617F-positive myeloproliferative neoplasms (MPNs), yet the mechanisms linking mutant hematopoiesis to CVD remain incompletely understood. We developed three complementary murine models to delineate the role of hematopoietic-endothelial crosstalk in JAK2V617F-associated CVD. In Model 1, which expresses JAK2V617F in both hematopoietic cells and endothelial cells (ECs), mice develop spontaneous dilated cardiomyopathy, right ventricular and microvascular thrombosis, arteriolar stenosis, and an increased risk of sudden death in the absence of external stressors. Model 2, with endothelial-restricted expression, develops cardiac dysfunction only under a high-fat diet, accompanied by microvascular thrombosis and arteriolar stenosis, without any increased risk of sudden death. Model 3, with mutant hematopoiesis alone, exhibits subtle baseline microvascular remodeling and endothelial inflammation, but progresses under a high-fat diet to a phenotype resembling heart failure with preserved ejection fraction, marked by arteriolar stenosis, perivascular fibrosis, endocardial injury, and relatively preserved systolic function. Across all three models, inflammatory signaling and endothelial-to-mesenchymal transition pathways are consistently activated in cardiac ECs. Notably, endocardial ECs in Model 3 display pronounced transcriptional reprogramming and structural disruption. Mechanistically, thrombopoietin/MPL signaling emerges as a key mediator of hematopoietic-endothelial crosstalk, and its inhibition attenuates JAK2V617F-driven cardiovascular pathology. Collectively, these findings establish a unified framework for JAK2V617F-associated CVD and identify endothelial MPL signaling as a promising therapeutic target.
PMID:42567442 | DOI:10.1016/j.ajpath.2026.07.005