Targeting TPO/MPL Signaling to Mitigate JAK2V617F-driven Cardiac Microvascular Disease

Area of Science:

• Cardiovascular Biology
• Hematology
• Molecular Medicine

Background:

• Individuals with JAK2V617F-mutant myeloproliferative neoplasms (MPNs) or clonal hematopoiesis of indeterminate potential (CHIP) face a significantly higher risk of cardiovascular disease.
• The precise mechanisms linking mutant blood cells to vascular and cardiac dysfunction are not fully understood.
• The thrombopoietin (TPO) receptor, MPL, is crucial for hematopoiesis and present in vascular endothelial cells (ECs), but its role in JAK2V617F-associated cardiovascular complications remains unclear.

Purpose of the Study:

• To investigate the role of JAK2V617F-mutant blood cells in driving cardiovascular complications.
• To explore the function of MPL signaling in endothelial cells within the context of JAK2V617F-driven cardiovascular disease.
• To assess the therapeutic potential of targeting MPL signaling in mitigating cardiac pathology.

Main Methods:

• Generation of chimeric mice with JAK2V617F-mutant blood cells and wild-type endothelium via bone marrow transplantation.
• Modeling cardiometabolic stress using a high-fat/high-cholesterol diet.
• Comprehensive analysis including histology, single-cell RNA sequencing, and immunohistochemistry.
• Intervention with an anti-MPL neutralizing antibody to assess therapeutic effects.

Main Results:

• JAK2V617F chimeric mice exhibited a unique cardiovascular phenotype, including microvascular disease, increased left ventricular mass, and coronary arteriole stenosis.
• Single-cell RNA sequencing identified activated inflammatory and endothelial-to-mesenchymal transition gene signatures in endocardial ECs.
• MPL expression was prominent in endocardial ECs, with upregulated TPO/MPL signaling in mutant hematopoiesis.
• Anti-MPL antibody treatment significantly improved cardiac pathology, restored endocardial integrity, and enhanced coronary microvascular density.

Conclusions:

• JAK2V617F-mutant hematopoiesis directly induces coronary microvascular dysfunction.
• Endocardial ECs are a critical cellular target in cardiometabolic stress associated with JAK2V617F.
• Targeting endocardial MPL signaling presents a promising therapeutic strategy for JAK2V617F-associated cardiovascular disease.