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Background <p>The attenuation of cellular phenotypic switchingdriving PAH vascular remodeling remains an unmet therapeutic need. As eNAMPT (nicotinamide phosphoribosyltransferase)/TLR4 signaling significantly contributes to PH pathobiology, an eNAMPT-neutralizing ALT-100 mAb was utilized to rescue monocrotaline (MCT) and hypoxia/Sugen (Hy/Su) preclinical PH rat models and to evaluate eNAMPT/TLR4 involvement in endothelial cell (EC), smooth muscle cell (SMC) and monocyte/macrophage phenotypic switching.</p> Methods <p>MCT-PH or Hy/Su-PH rats received IgG or ALT-100 mAb (subQ, beginning week 4) with measurements of PH severity and lung tissue scRNAseq at day 42.</p> Results <p>PH severity indices (hemodynamic, histologic, vascular remodeling) were significantly attenuated in MCT-PH and Hy/Su-PH rats receiving ALT-100 mAb. scRNAseq studies revealed Hy/Su exposure increased populations of ECs undergoing EC-to-mesenchymal cell transition (EndMT), proliferating SMCs, and monocytes undergoing macrophage differentiation. Cellular phenotypic switching was ameliorated in Hy/Su-mAb rats.</p> Conclusions <p>Autocrine/paracrine eNAMPT/TLR4 signaling contributes to accelerated cellular phenotypic switching, a druggable strategy to reverse vascular remodeling.</p>

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eNAMPT/TLR4 signaling drives PAH cellular phenotypic switching and lung vascular remodeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月29日

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  • Mohamed Ahmed,
  • Shaira L. Kee,
  • Nahla Zaghloul,
  • Nancy G. Casanova,
  • Marisela Rodriguez,
  • Carrie L. Kempf,
  • Sara M. Camp,
  • Jin H. Song,
  • Saad Sammani,
  • Akash Gupta,
  • Andrew J. Bryant,
  • Aikseng Ooi,
  • Ankit A. Desai,
  • Ayako Makino,
  • Jason X.-J. Yuan,
  • Panayiotis V. Benos,
  • Zhiyu Dai,
  • Joe G. N. Garcia

摘要

Background

The attenuation of cellular phenotypic switchingdriving PAH vascular remodeling remains an unmet therapeutic need. As eNAMPT (nicotinamide phosphoribosyltransferase)/TLR4 signaling significantly contributes to PH pathobiology, an eNAMPT-neutralizing ALT-100 mAb was utilized to rescue monocrotaline (MCT) and hypoxia/Sugen (Hy/Su) preclinical PH rat models and to evaluate eNAMPT/TLR4 involvement in endothelial cell (EC), smooth muscle cell (SMC) and monocyte/macrophage phenotypic switching.

Methods

MCT-PH or Hy/Su-PH rats received IgG or ALT-100 mAb (subQ, beginning week 4) with measurements of PH severity and lung tissue scRNAseq at day 42.

Results

PH severity indices (hemodynamic, histologic, vascular remodeling) were significantly attenuated in MCT-PH and Hy/Su-PH rats receiving ALT-100 mAb. scRNAseq studies revealed Hy/Su exposure increased populations of ECs undergoing EC-to-mesenchymal cell transition (EndMT), proliferating SMCs, and monocytes undergoing macrophage differentiation. Cellular phenotypic switching was ameliorated in Hy/Su-mAb rats.

Conclusions

Autocrine/paracrine eNAMPT/TLR4 signaling contributes to accelerated cellular phenotypic switching, a druggable strategy to reverse vascular remodeling.