Advances in wound care · 2026
Reimagining VEGF Therapy: The Role of PLCγ2 in Pan-Organ Endothelial Networks.
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Abouhashem Ahmed S, Verma Sumit S, Faden-McCormack Julie, Moqidem Yomna A, Dutta Partha, Sen Chandan K, Singh Kanhaiya
Аннотация
OBJECTIVE: Ischemic tissue perfusion remains a major clinical challenge despite VEGF's central role in angiogenesis. Limited success of VEGF-based therapies underscores the need to understand endothelial heterogeneity, as distinct subsets exhibit differential responsiveness. This study explores conserved endothelial states that govern VEGF-driven angiogenesis across human organs and evaluates their functional significance.
APPROACH: We performed single-cell and single-nucleus RNA-sequencing (scRNA-seq/snRNA-seq) analysis of endothelial cells (ECs) from eight human tissues using GTEx data, validated findings in independent skin and heart datasets, and conducted CRISPR-mediated PLCγ2 knockout in cultured ECs followed by scRNA-seq.
RESULTS: Analysis of 209,126 nuclei revealed a universal arterial-like endothelial subset (cluster 2) enriched across all organs, characterized by high expression of PLCγ2, a critical VEGF signaling effector. PLCγ2high cells exhibited robust angiogenic and lymphangiogenic programs, including upregulation of VEGFC, NOTCH4, and JAG1, and enrichment of pathways for vasculature development and endothelial differentiation. Cell-cell communication analysis demonstrated exclusive BMP6, IGF2, and CXCL12 signaling from PLCγ2high cells to fibroblasts, pericytes, and immune cells, positioning this subset as a central angiogenic hub. Functional validation showed that PLCγ2 knockout depleted PLCγ2high clusters, suppressed VEGF signaling, and diminished BMP6 ligand secretion, confirming its role in maintaining proangiogenic endothelial states.
INNOVATION: Ineffective targeting of the appropriate EC state may limit current therapeutic VEGF strategies, positioning PLCγ2high ECs as a clinically relevant target.
CONCLUSION: We identify PLCγ2high arterial ECs as a conserved pan-organ population critical for VEGF responsiveness and vascular regeneration. These findings reimagine VEGF therapy by highlighting PLCγ2 as a critical regulator of a proangiogenic arterial-like endothelial state and a promising combinatorial target to overcome limitations of current angiogenic strategies.
APPROACH: We performed single-cell and single-nucleus RNA-sequencing (scRNA-seq/snRNA-seq) analysis of endothelial cells (ECs) from eight human tissues using GTEx data, validated findings in independent skin and heart datasets, and conducted CRISPR-mediated PLCγ2 knockout in cultured ECs followed by scRNA-seq.
RESULTS: Analysis of 209,126 nuclei revealed a universal arterial-like endothelial subset (cluster 2) enriched across all organs, characterized by high expression of PLCγ2, a critical VEGF signaling effector. PLCγ2high cells exhibited robust angiogenic and lymphangiogenic programs, including upregulation of VEGFC, NOTCH4, and JAG1, and enrichment of pathways for vasculature development and endothelial differentiation. Cell-cell communication analysis demonstrated exclusive BMP6, IGF2, and CXCL12 signaling from PLCγ2high cells to fibroblasts, pericytes, and immune cells, positioning this subset as a central angiogenic hub. Functional validation showed that PLCγ2 knockout depleted PLCγ2high clusters, suppressed VEGF signaling, and diminished BMP6 ligand secretion, confirming its role in maintaining proangiogenic endothelial states.
INNOVATION: Ineffective targeting of the appropriate EC state may limit current therapeutic VEGF strategies, positioning PLCγ2high ECs as a clinically relevant target.
CONCLUSION: We identify PLCγ2high arterial ECs as a conserved pan-organ population critical for VEGF responsiveness and vascular regeneration. These findings reimagine VEGF therapy by highlighting PLCγ2 as a critical regulator of a proangiogenic arterial-like endothelial state and a promising combinatorial target to overcome limitations of current angiogenic strategies.