Endothelial TLR4 coordinates angiogenesis and inflammation through a CXCR2–neutrophil–oxidative axis

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ID: 329828
2026
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Abstract
AIMS: To determine the endothelial-intrinsic role of TLR4 in inflammatory vascular remodeling and cytokine signaling, and to define how exogenous microbial and oxidation-derived endogenous signals are integrated by endothelial TLR4 to regulate vascular function. METHODS AND RESULTS: Single-cell transcriptomic analyses of human tissues identified endothelial cells as a coherent, lineage-consistent TLR4-expressing population across tissues and disease states, distinguishing TLR4 from other endothelial Toll-like receptors. Using tamoxifen-inducible endothelial-specific TLR4 knockout mice (Cdh5-CreERT2; Tlr4flox/flox) we show that lack of TLR4 markedly impaired early venular remodeling, junctional loosening, vascular leakage, and neutrophil recruitment during skin wound healing, and suppressed tumor angiogenesis and growth in a syngeneic cancer model. Mechanistically, endothelial TLR4 activation induced a focused chemokine program dominated by CXCL1/2/5-CXCR2 signaling, promoting neutrophil recruitment and lipid-oxidation responses. Loss of endothelial TLR4 reduced myeloperoxidase (MPO)-positive inflammatory-cell accumulation and carboxyethylpyrrole lipid-peroxidation adduct deposition, supporting a feed-forward inflammatory loop in which neutrophil-derived oxidized lipids act as endogenous TLR4 ligands. Pharmacologic CXCR2 inhibition or combined ROS/MPO suppression phenocopied endothelial TLR4 deletion. CONCLUSIONS: Endothelial-intrinsic TLR4 functions as a vascular inflammatory integrator that links microbial pattern recognition with endogenous oxidation-derived danger signaling to coordinate chemokine production, neutrophil recruitment, MPO-linked lipid-oxidation amplification, and angiogenesis. These findings identify endothelial TLR4 as a distinct and targetable vascular inflammatory node, functionally separable from hematopoietic TLR4, with implications for sterile inflammatory cardiovascular disease.
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Authors Iuliia Molokotina, Josh Ford, Olha Kyrychek, Irina Zhevlakova, Moses Lee, Eugene A. Podrez, Anish Korrapati, Olga A. Cherepanova, Tatiana V. Byzova
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Journal cardiovascular research
Year 2026
DOI
10.1093/cvr/cvag211
URL
https://doi.org/10.1093/cvr/cvag211
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