JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic...

Area of Science:

• Cardiovascular Biology
• Hematology
• Immunology

Background:

• The JAK2V617F mutation is linked to cardiovascular disease but its role in aortic disease is unclear.
• Myeloproliferative neoplasms (MPNs) are associated with increased thrombotic risk.

Purpose of the Study:

• To investigate the role of JAK2V617F mutation in thoracic aortic aneurysm development and complications.
• To elucidate the cellular and molecular mechanisms underlying JAK2V617F-driven aortic disease.

Main Methods:

• Analysis of a patient cohort with myeloproliferative neoplasms.
• Single-cell RNA sequencing (scRNA-seq) of aortic tissue.
• Genetically-modified mouse models and pharmacological interventions.
• In vivo and in vitro studies of macrophage phenotypes and function.

Main Results:

• JAK2V617F mutation is an independent risk factor for ascending and descending thoracic aortic dilation.
• The mutation induces a pro-inflammatory phenotype in perivascular tissue-resident macrophages.
• This leads to aortic wall remodeling and dissecting aneurysms via monocyte recruitment.
• Genetic modulation of macrophages or Jak2 inhibition (ruxolitinib) reduced aortic inflammation and pathology.

Conclusions:

• JAK2V617F mutation drives pathogenic changes in vascular resident macrophages, promoting dissecting aortic aneurysms.
• Targeting tissue-resident macrophages or Jak2 signaling offers potential therapeutic strategies for aortic complications in MPNs.