A tissue-resolved endothelial surface proteome atlas informs organ-selective vascular targeting
BACKGROUND Endothelial cells (ECs) exhibit organ-specific functional diversity that shapes vascular homeostasis, disease susceptibility, and therapeutic accessibility. Although single-cell transcriptomic studies have defined endothelial heterogeneity at the RNA level, the in vivo cell-surface protein landscape that directly mediates vascular signaling and drug targeting remains incompletely…
Endothelial cells display distinct functional roles across different organs, influencing vascular health, disease risk, and drug delivery. While single-cell RNA studies have mapped endothelial diversity, the protein composition on cell surfaces that governs vascular signaling and targeted drug delivery has not been thoroughly explored.
To address this gap, researchers developed a technique called Cdh5-CreERT; Cre-iPEEL mice, designated as CHRP mice. These mice were engineered to activate membrane-tethered horseradish peroxidase specifically in endothelial cells following tamoxifen treatment.
By comparing CHRP labeling with a non-selective NHS-Biotin method, the CHRP approach demonstrated enhanced endothelial specificity, resulting in distinct separation of tissue-specific protein profiles in various organs such as the brain, white adipose tissue, small intestine, kidney, lung, and skeletal muscle. The CHRP proteomics analysis unveiled pronounced organ-specific heterogeneity, identifying canonical arterial, venous, and capillary programs, as well as specialized endothelial signatures for the blood-brain barrier and glomerular endothelium.
Comparing CHRP proteomics with single-cell RNA references highlighted discrepancies in the detection of endothelial membrane proteins, underscoring the complementary nature of these two approaches. Furthermore, the study identified tissue-selective endothelial membrane candidates and linked a subset of these candidates to existing compounds in the ChEMBL database, establishing a valuable resource for future research into tissue-selective vascular targeting strategies.
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