Macrophages Promote Aortic Valve Cell Calcification and Alter STAT3 Splicing

Area of Science:

• Cardiovascular Biology
• Immunology
• Genetics

Background:

• Macrophages are present in calcific aortic valve disease (CAVD), but their role in promoting or counteracting calcification remains unclear.
• The Notch1 signaling pathway is implicated in CAVD pathogenesis.

Purpose of the Study:

• To investigate the role of macrophages in CAVD using the Notch1+/- mouse model.
• To determine if macrophage differences drive disease progression in CAVD.
• To elucidate the interaction between aortic valve cells and macrophages in the context of calcification.

Main Methods:

• Flow cytometry to characterize macrophages in wild-type and Notch1+/- murine aortic valves.
• Bone marrow transplantation experiments to assess the contribution of macrophage genotype to disease.
• In vitro co-culture systems to study aortic valve cell-macrophage interactions.
• Analysis of macrophage infiltration, proinflammatory phenotypes (Ly6C, CCR2), and calcification.

Main Results:

• Notch1+/- aortic valves exhibited increased macrophage infiltration and proinflammatory maturation (MHCII expression).
• Notch1+/- aortic valve cells promoted macrophage invasion and proinflammatory phenotypes independently of macrophage genotype.
• Macrophage interaction with aortic valve cells enhanced osteogenic calcification and reduced STAT3β isoform abundance.

Conclusions:

• Notch1+/- aortic valve disease is characterized by increased macrophage recruitment and maturation, driven by aortic valve cell secretions.
• Macrophage recruitment promotes osteogenic calcification and alters STAT3 splicing in CAVD.
• STAT3 and macrophage-driven inflammation represent promising therapeutic targets for CAVD.