PDGFRA in vascular adventitial MSCs promotes neointima formation in arteriovenous fistula in chronic kidney disease

Chronic kidney disease (CKD) induces the failure of arteriovenous fistulas (AVF) and promotes the differentiation of vascular adventitial GLI1+ mesenchymal stem cells (GMCs). However, the roles of GMCs in forming neointima in AVFs remains unknown. GMCs isolated from CKD mice showed increased potential capacity of differentiation into myofibroblast-like cells. Increased activation of expression of PDGFRA and hedgehog (HH) signaling were detected in adventitial cells of AVFs from ESRD patients and CKD mice. PDGFRA was translocated and accumulated in early endosome when hedgehog signaling stimulates was activated. In endosome, PDGFRA mediated activation of TGFB1/SMAD signaling promoting GMCs differentiation into myofibroblast, extracellular matrix deposition, and vascular fibrosis. These responses resulted in neointima formation and AVF failure. Knockout (KO) of Pdgfra or inhibition of HH signaling in GMCs suppressed the differentiation of GMCs into myofibroblasts. In vivo, specific KO of Pdgfra inhibited GMC activation and vascular fibrosis, resulting in suppression of neointima formation and improvement of AVF patency despite CKD. Our findings could yield strategies for maintaining AVF functions.