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<p>To model selected hypoxia-associated features of keloid-like fibroblast remodeling, this study used normal human dermal fibroblasts exposed to hypoxia, with TGF-β1 stimulation used to establish a profibrotic fibroblast phenotype. Hypoxia is a hallmark of keloid tissues and contributes to fibroblast dysfunction and abnormal vascular remodeling. However, the molecular mechanisms linking hypoxia to fibroblast activation and paracrine angiogenesis remain unclear. Here, using normal human dermal fibroblasts as an in vitro approximation of hypoxia-associated keloid-like remodeling, we show that hypoxia activates DLL4/NOTCH and endothelin (EDN1) signaling. Loss-of-function assays showed that DLL4 and EDN1 are required to maintain hypoxia-associated fibroblast proliferation, survival, migration, and fibrotic remodeling. Conditioned medium from hypoxic fibroblasts enhanced endothelial tube formation and migration, whereas these responses were attenuated when conditioned medium was obtained from DLL4- or EDN1-silenced fibroblasts. These findings indicate that fibroblast DLL4/NOTCH and EDN1 signaling influence the hypoxia-conditioned secretome, although the relative contributions of EDN1, VEGF, and other soluble mediators were not resolved. Loss-of-function and pharmacological inhibition experiments showed that full EDN1 expression and secretion under hypoxia depended on DLL4-associated NOTCH activity, with NOTCH1 contributing functionally to this response; however, involvement of other NOTCH receptors was not examined. Recombinant EDN1 partially restored proliferation, migration, and angiogenic support in DLL4-deficient fibroblasts. These findings support functional coupling between DLL4-associated NOTCH and EDN1 signaling but do not establish direct transcriptional regulation of EDN1 by NOTCH. Furthermore, asymmetric functional coupling between DLL4/NOTCH and EDN1 pathways. This study shows that hypoxia induces coordinated DLL4/NOTCH and EDN1 signaling in dermal fibroblasts and that EDN1 mediates part of the DLL4-associated fibroblast activation and endothelial-supportive phenotype.</p>

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Hypoxia-activated DLL4/NOTCH–EDN1 signaling maintains fibroblast activation and endothelial crosstalk in a human dermal fibroblast model of keloid-like remodeling

  • 期刊论文

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  • 发表日期：

    2026年7月29日

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  • Shenxi Zhang,
  • Xue Zhang,
  • Xiaoyang Wang

摘要

To model selected hypoxia-associated features of keloid-like fibroblast remodeling, this study used normal human dermal fibroblasts exposed to hypoxia, with TGF-β1 stimulation used to establish a profibrotic fibroblast phenotype. Hypoxia is a hallmark of keloid tissues and contributes to fibroblast dysfunction and abnormal vascular remodeling. However, the molecular mechanisms linking hypoxia to fibroblast activation and paracrine angiogenesis remain unclear. Here, using normal human dermal fibroblasts as an in vitro approximation of hypoxia-associated keloid-like remodeling, we show that hypoxia activates DLL4/NOTCH and endothelin (EDN1) signaling. Loss-of-function assays showed that DLL4 and EDN1 are required to maintain hypoxia-associated fibroblast proliferation, survival, migration, and fibrotic remodeling. Conditioned medium from hypoxic fibroblasts enhanced endothelial tube formation and migration, whereas these responses were attenuated when conditioned medium was obtained from DLL4- or EDN1-silenced fibroblasts. These findings indicate that fibroblast DLL4/NOTCH and EDN1 signaling influence the hypoxia-conditioned secretome, although the relative contributions of EDN1, VEGF, and other soluble mediators were not resolved. Loss-of-function and pharmacological inhibition experiments showed that full EDN1 expression and secretion under hypoxia depended on DLL4-associated NOTCH activity, with NOTCH1 contributing functionally to this response; however, involvement of other NOTCH receptors was not examined. Recombinant EDN1 partially restored proliferation, migration, and angiogenic support in DLL4-deficient fibroblasts. These findings support functional coupling between DLL4-associated NOTCH and EDN1 signaling but do not establish direct transcriptional regulation of EDN1 by NOTCH. Furthermore, asymmetric functional coupling between DLL4/NOTCH and EDN1 pathways. This study shows that hypoxia induces coordinated DLL4/NOTCH and EDN1 signaling in dermal fibroblasts and that EDN1 mediates part of the DLL4-associated fibroblast activation and endothelial-supportive phenotype.