Background: Peripheral artery disease (PAD) affects millions worldwide, yet the immune mechanisms governing successful adaptation to vascular occlusion remain incompletely understood. While traditional risk factors predict atherosclerotic burden, clinical symptoms vary dramatically among patients with comparable vessel stenosis, suggesting that endogenous compensatory mechanisms—particularly immune-mediated revascularization—determine disease severity. CD11c-expressing myeloid cells have emerged as critical orchestrators of tissue repair and angiogenesis in ischemic conditions.
Methods: In the LUERPAD-Immuno study, we performed large-scale screening of 4,000 patients to identify a unique cohort of asymptomatic high-grade PAD patients (sHG-PAD, n=21) with proven arterial stenosis but complete absence of claudication symptoms. These were matched with symptomatic PAD patients (cHG-PAD, n=19) exhibiting identical ankle-brachial indices but severe walking impairment. High-dimensional flow cytometry with AI-based clustering, single-cell RNA sequencing, and comprehensive plasma proteomics were employed to dissect immune signatures. Mechanistic validation was performed using CD11c-DTR transgenic mice in a hindlimb ischemia model with temporal assessment of revascularization, gene expression profiling, and functional CD11c+ cell depletion experiments.
Results: CD11c-high monocytes were significantly elevated in symptomatic versus asymptomatic PAD patients (p<0.01), representing a paradoxical inflammatory signature associated with impaired adaptation. This subset exhibited activation markers CD40 and CD202b, suggesting enhanced antigen-presenting capacity. Notably, plasma TIMP-1 levels—a multifunctional metalloproteinase inhibitor regulating angiogenesis—were markedly elevated in cHG-PAD patients and strongly correlated with CD11c-high monocyte frequency. In murine hindlimb ischemia, CD11c+ cells infiltrated ischemic tissue as early as 24 hours post-ligation, establishing them as primary responders. Gene expression analysis revealed significant upregulation of TIMP1, HGF, and CXCL10 in wildtype but not CD11c-depleted mice. Critically, CD11c+ cell depletion resulted in profoundly impaired revascularization with reduced capillary density and diminished pericyte coverage, demonstrating functional necessity for tissue repair. Mechanistically, CD11c+ cells appear to modulate extracellular matrix remodeling through TIMP-1 delivery to ischemic tissues, with excessive TIMP-1 levels potentially inhibiting optimal matrix metalloproteinase activity required for angiogenic sprouting.
Conclusions: This translational study unveils CD11c-high monocytes as double-edged regulators of ischemic revascularization in PAD. While CD11c+ cells are essential early responders promoting vascular repair, their pathological expansion and associated TIMP-1 overexpression paradoxically impairs neovascularization, explaining symptom severity despite comparable anatomical disease. These findings identify CD11c-high monocytes and the TIMP-1/MMP axis as promising biomarkers for risk stratification and novel therapeutic targets to enhance collateral formation in PAD patients. The paradigm of leveraging asymptomatic PAD patients as a model for successful vascular adaptation represents a powerful approach to decode protective immune mechanisms with broad implications for ischemic cardiovascular diseases.
