DDR1 Regulates Femoral Arterial Calcification in Lower-Extremity Artery Disease Through NF-Kappa B Activation.
Publisher DOI
PubMed ID
41399911
Abstract
Aim
Lower-extremity arterial disease (LEAD) is a manifestation of atherosclerotic cardiovascular disease, affecting 230 million people worldwide with increasing prevalence. Medial arterial calcification (MAC) is common in LEAD patients and contributes to disease-related mortality. However, therapeutic strategies targeting femoral MAC are lacking, and its underlying mechanisms remain unclear. This study aimed to identify molecular drivers of femoral MAC in LEAD.Methods & Results
Calcium deposits and pro-calcifying markers were analyzed in human patient samples using von Kossa staining, immunofluorescence, and gene expression analysis. Femorals showed significantly more calcification and pro-calcifying gene expression than carotids. Given MAC abundance in LEAD, we assessed medial calcification in Apoe-/- mice fed a WD for 4/21 weeks. Digital PCR revealed upregulation of Ddr1 and Bmp2 in femoral versus carotid arteries after 21 weeks of WD. DDR1 expression positively correlated with calcification in human femoral samples. In vitro experiments with mouse femoral vs. carotid vascular smooth muscle cells (VSMCs) confirmed a significantly higher prevalence of calcifying proteins (DDR1, BMP2, and RUNX2) in femoral VSMCs. Additionally, calcification analyses in murine and human VSMCs showed that DDR1 inhibition reduced, while DDR1 activation increased, calcium deposition. Transcriptomic analysis revealed elevated NF-κB expression in human femoral arteries, matching data in femoral VSMCs. DDR1 stimulation activated NF-κB, and its inhibition blocked DDR1-induced calcification.Conclusion
This study identifies DDR1 as a key driver of calcification in LEAD, operating through NF-κB activation and the expression of calcifying proteins. Targeting DDR1 may offer a novel therapeutic approach to prevent MAC in LEAD.
Lower-extremity arterial disease (LEAD) is a manifestation of atherosclerotic cardiovascular disease, affecting 230 million people worldwide with increasing prevalence. Medial arterial calcification (MAC) is common in LEAD patients and contributes to disease-related mortality. However, therapeutic strategies targeting femoral MAC are lacking, and its underlying mechanisms remain unclear. This study aimed to identify molecular drivers of femoral MAC in LEAD.Methods & Results
Calcium deposits and pro-calcifying markers were analyzed in human patient samples using von Kossa staining, immunofluorescence, and gene expression analysis. Femorals showed significantly more calcification and pro-calcifying gene expression than carotids. Given MAC abundance in LEAD, we assessed medial calcification in Apoe-/- mice fed a WD for 4/21 weeks. Digital PCR revealed upregulation of Ddr1 and Bmp2 in femoral versus carotid arteries after 21 weeks of WD. DDR1 expression positively correlated with calcification in human femoral samples. In vitro experiments with mouse femoral vs. carotid vascular smooth muscle cells (VSMCs) confirmed a significantly higher prevalence of calcifying proteins (DDR1, BMP2, and RUNX2) in femoral VSMCs. Additionally, calcification analyses in murine and human VSMCs showed that DDR1 inhibition reduced, while DDR1 activation increased, calcium deposition. Transcriptomic analysis revealed elevated NF-κB expression in human femoral arteries, matching data in femoral VSMCs. DDR1 stimulation activated NF-κB, and its inhibition blocked DDR1-induced calcification.Conclusion
This study identifies DDR1 as a key driver of calcification in LEAD, operating through NF-κB activation and the expression of calcifying proteins. Targeting DDR1 may offer a novel therapeutic approach to prevent MAC in LEAD.
Date Issued
2026-01
Publication Type
Article
Subject(s)
Subjects
DDR1
•
LEAD‐specific calcification
•
femoral vascular smooth muscle cell
•
medial arterial calcification
Language(s)
en
Author(s)
Quillard, Thibaut | |
Jansen, Yvonne | |
Yan, Yi | |
Wollenhaupt, Julia | |
Goettsch, Claudia | |
Maegdefessel, Lars | |
Sachs, Nadia | |
Noels, Heidi |
Journal
Acta Physiologica
Publisher
Wiley
ISSN
1748-1716
1748-1708
Related Collection(s)
Access(Rights)
open.access