Endothelial Integrin-Linked Kinase (ILK) Deficiency Promotes Endothelial Activation and Cardiovascular Dysfunction...

Area of Science:

• Cardiovascular Biology
• Cell Biology
• Molecular Medicine

Background:

• Integrin-linked kinase (ILK) is crucial for endothelial homeostasis and vascular health.
• Endothelial ILK deficiency is linked to vascular and cardiac diseases, but underlying mechanisms are poorly understood.
• Extracellular vesicles (EVs) are implicated in intercellular communication and disease pathogenesis.

Purpose of the Study:

• To investigate the role of EVs released from ILK-deficient endothelial cells in propagating endothelial activation and cardiac dysfunction.
• To elucidate the molecular mechanisms, particularly the involvement of receptor-interacting protein kinase 1 (RIPK1), in ILK-mediated EV signaling.
• To determine if the identified ILK-RIPK1 EV axis is relevant in models of atherosclerosis and human coronary artery disease.

Main Methods:

• Endothelial-specific ILK conditional knockout mice were generated to study ILK loss.
• In vitro experiments assessed endothelial cell function, NF-κB activation, and chemokine production.
• EVs were isolated from ILK-deficient and wild-type cells, and their cargo and functional effects were analyzed.
• RIPK1 inhibition and silencing were used to confirm its role in EV-mediated signaling.
• EV transfer studies were performed in wild-type mice to assess cardiac and vascular effects.
• EVs from atherosclerotic mice and human samples were analyzed for relevance.

Main Results:

• Endothelial ILK loss rapidly induced endothelial activation, inflammation, and cardiac dysfunction in mice.
• ILK-deficient endothelial cells exhibited barrier dysfunction and released EVs enriched in RIPK1.
• These EVs transferred an activation phenotype to naïve endothelial cells in a RIPK1-dependent manner.
• Transfer of EVs from ILK-deficient mice induced vascular inflammation, fibrosis, and dysfunction in recipient wild-type mice.
• Similar RIPK1-dependent inflammatory effects were observed with EVs from atherosclerotic models and human coronary artery disease patients.

Conclusions:

• A novel ILK-RIPK1 extracellular vesicle (EV) signaling axis promotes vascular inflammation and cardiac dysfunction.
• This pathway represents a conserved mechanism in endothelial dysfunction, relevant to both experimental models and human atherosclerosis.
• Targeting the ILK-RIPK1 EV axis may offer therapeutic strategies for cardiovascular diseases.