BACE2-Induced Aberrant Lymphatic Network Aggravates the Local Inflammation in Arteriovenous Fistulas With...

Area of Science:

• Vascular biology
• Immunology
• Nephrology

Background:

• Arteriovenous fistulas (AVFs) are crucial for hemodialysis but suffer high failure rates due to inflammation.
• Chronic kidney disease (CKD) exacerbates AVF inflammation through unclear mechanisms.

Purpose of the Study:

• To investigate cellular changes and mechanisms of AVF remodeling in human and mouse models, particularly under CKD conditions.
• To identify novel strategies for improving AVF function in CKD patients.

Main Methods:

• Spatial transcriptomics and single-cell RNA sequencing were employed in human and mouse AVF models.
• Animal models with 5/6 nephrectomy were used to simulate CKD, alongside genetic manipulation (BACE2 knockout) and pharmacological inhibition.

Main Results:

• A lymphatic network, supported by Pi16+Vegfc+ fibro-progenitors, acts as an efflux pathway in AVFs.
• Hyperphosphatemia in CKD impairs lymphatic function by increasing soluble VEGFR3, reducing lymphatic endothelial cell (LEC) sensitivity to VEGF-C via SP1/BACE2/VEGFR3 cleavage.
• Restoring lymphatic function through BACE2 inhibition or knockout in mice alleviated AVF inflammation and neointima formation.

Conclusions:

• The lymphatic network is a critical, overlooked component in AVF health, especially in CKD.
• Targeting BACE2-mediated VEGFR3 cleavage offers a novel strategy to normalize lymphatic function, reduce inflammation, and improve AVF outcomes in CKD patients.