Blocking Notch in endothelial cells prevents arteriovenous fistula failure despite CKD.
Neointima formation causes the failure of 60% of arteriovenous fistulas (AVFs) within 2 years. Neointima-forming mechanisms are controversial but possibly linked to excess proinflammatory responses and dysregulated Notch signaling. To identify how AVFs fail, we anastomosed the carotid artery to the internal jugular vein in normal and uremic mice and compared these findings with those in failed AVFs from patients with ESRD. Endothelial cells (ECs) of AVFs in uremic mice or patients expressed mesenchymal markers (FSP-1 and/or α-SMA) and exhibited increased expression and nuclear localization of Notch intracellular domain compared with ECs of AVFs in pair-fed control mice. Furthermore, expression of VE-Cadherin decreased, whereas expression of Notch1 and -4, Notch ligands, the downstream transcription factor of Notch, RBP-Jκ, and Notch target genes increased in ECs of AVFs in uremic mice. In cultured ECs, ectopic expression of Notch ligand or treatment with TGF-β1 triggered the expression of mesenchymal markers and induced endothelial cell barrier dysfunction, both of which were blocked by Notch inhibition or RBP-Jκ knockout. Furthermore, Notch-induced defects in barrier function, invasion of inflammatory cells, and neointima formation were suppressed in mice with heterozygous knockdown of endothelial-specific RBP-Jκ. These results suggest that increased TGF-β1, a complication of uremia, activates Notch in endothelial cells of AVFs, leading to accelerated neointima formation and AVF failure. Suppression of Notch activation could be a strategy for improving AFV function in uremia.
Division of Nephrology, Baylor College of Medicine, Houston, Texas;
Yun
Y
Wang
Anlin
A
Liang
Jinlong
J
Luo
Ming
M
Liang
Guofeng
G
Han
William E
WE
Mitch
Jizhong
J
Cheng
D000199:Actins / Q000032:analysis; D000368:Aged; D000818:Animals; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D002135:Calcium-Binding Proteins / Q000032:analysis; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000502:physiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D058426:Neointima; D051880:Receptors, Notch / Q000502:physiology*; D051436:Renal Insufficiency, Chronic / Q000473:pathology / Q000503:physiopathology*; D000071999:S100 Calcium-Binding Protein A4; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000502:physiology
C541116:ACTA2 protein, human; D000199:Actins; D002135:Calcium-Binding Proteins; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D051880:Receptors, Notch; D000071999:S100 Calcium-Binding Protein A4; D053773:Transforming Growth Factor beta1; C077591:S100A4 protein, human