L-Wnk1 Deletion in Smooth Muscle Cells Causes Aortitis and Inflammatory Shift

Area of Science:

• Cardiovascular Biology
• Molecular Biology
• Immunology

Background:

• The long isoform of with-no-lysine 1 kinase (Wnk1) is a ubiquitous serine/threonine kinase.
• The role of Wnk1 in vascular smooth muscle cell (VSMC) pathophysiology is largely unknown.

Purpose of the Study:

• To investigate the functional role of Wnk1 in VSMCs, particularly in the context of vascular remodeling and aneurysm formation.
• To determine the impact of Wnk1 deletion on VSMC phenotype and inflammatory responses.

Main Methods:

• Utilized a mouse model with VSMC-specific Wnk1 deletion (Sm22Cre+Wnk1flox/flox).
• Induced experimental aortic aneurysm using angiotensin II infusion in Apoe-/- mice.
• Performed single-cell RNA-sequencing to analyze VSMC gene expression in aneurysmal aortas.
• Investigated the effects of Wnk1 deletion on VSMC contractile function, inflammatory mediator production, and immune cell infiltration.
• Assessed the impact of Wnk1 deletion on aortic wall structure and extracellular matrix composition.
• Evaluated the therapeutic potential of blocking specific immune pathways (γδ T cells, monocyte/macrophage) and TGF-β signaling.

Main Results:

• Single-cell RNA-sequencing revealed that Wnk1-deficient VSMCs exhibit a reduced contractile phenotype and increased inflammatory activity.
• Wnk1 deletion in VSMCs resulted in a proinflammatory phenotype, characterized by matrix metalloproteinase and cytokine/chemokine production, leading to immune cell accumulation.
• Sm22Cre+Wnk1flox/flox mice spontaneously developed severe aortitis and, upon AngII infusion, lethal abdominal aortic aneurysms.
• Pharmacological blockade of γδ T cells or monocyte/macrophage recruitment attenuated aortitis.
• Wnk1 deletion induced aortic wall remodeling, including elastin destruction and increased collagen deposition, alongside enhanced TGF-β1 expression.
• TGF-β blockade exacerbated aneurysm formation and aorta rupture in Wnk1-deficient mice.

Conclusions:

• Wnk1 is a critical regulator of VSMC function.
• Wnk1 deletion promotes a pathogenic, proinflammatory VSMC phenotype.
• Wnk1 deficiency orchestrates detrimental vascular remodeling and spontaneous severe aortitis in mice.