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

Xiaoxi Yang^1,2, Kyla Masarik¹, Xiaochuan Sun^1,2

¹Department of Medicine, Stony Brook School of Medicine, Stony Brook, NY, United States.

Biorxiv : the Preprint Server for Biology

|April 10, 2026

Insights

JAK2V617F-mutant blood cells cause cardiovascular disease by affecting microvasculature. Targeting MPL signaling in endocardial cells may treat these JAK2V617F-associated heart conditions.

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.

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Abstract

Background:

Individuals with JAK2V617F-mutant myeloproliferative neoplasms or clonal hematopoiesis of indeterminate potential have a markedly increased risk of cardiovascular disease, yet the mechanisms by which mutant blood cells drive vascular and cardiac dysfunction remain incompletely understood. Although the thrombopoietin (TPO) receptor MPL is central to hematopoiesis and is expressed in vascular endothelial cells (ECs), its role in JAK2V617F-associated cardiovascular complications is unknown.

Methods And Results:

We generated chimeric mice with JAK2V617F-mutant blood cells and wild-type endothelium by bone marrow transplantation and challenged them with a high-fat/high-cholesterol diet to model cardiometabolic stress. These mice developed a distinct cardiovascular phenotype characterized by microvascular disease, increased left ventricular mass, and relatively preserved left ventricular ejection fraction. Histological analysis revealed coronary arteriole stenosis, perivascular fibrosis, reduced microvascular density, and endocardial injury, without evidence of epicardial coronary stenosis or myocardium infarction.Single-cell RNA sequencing revealed activation of inflammatory, stress-response, and endothelial-to-mesenchymal transition gene signatures in ECs, most prominently within the endocardial ECs. Immunohistochemistry identified MPL expression predominantly in endocardial ECs. TPO/MPL signaling was upregulated in endocardial ECs in mice with JAK2V617F-mutant hematopoiesis, and treatment with an anti-MPL neutralizing antibody markedly improved cardiac pathology, restored endocardial integrity, and increased coronary microvascular density despite persistent systemic inflammation.

Conclusions:

JAK2V617F-mutant hematopoiesis induces coronary microvascular dysfunction. Endocardial ECs represent a key cellular target under cardiometabolic stress, and endocardial MPL signaling constitutes a potential targetable pathway in JAK2V617F-associated cardiovascular disease.

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