Nonfunctional TGF-β/ALK1/ENG signaling pathway supports neutrophil proangiogenic activity in hereditary hemorrhagic telangiectasia

J Leukoc Biol. 2023 Nov 24;114(6):639-650. doi: 10.1093/jleuko/qiad090.

Abstract

The transforming growth factor β (TGF-β)/ALK1/ENG signaling pathway maintains quiescent state of endothelial cells, but at the same time, it regulates neutrophil functions. Importantly, mutations of this pathway lead to a rare autosomal disorder called hereditary hemorrhagic telangiectasia (HHT), characterized with abnormal blood vessel formation (angiogenesis). As neutrophils are potent regulators of angiogenesis, we investigated how disturbed TGF-β/ALK1/ENG signaling influences angiogenic properties of these cells in HHT. We could show for the first time that not only endothelial cells, but also neutrophils isolated from such patients are ENG/ALK1 deficient. This deficiency obviously stimulates proangiogenic switch of such neutrophils. Elevated proangiogenic activity of HHT neutrophils is mediated by the increased spontaneous degranulation of gelatinase granules, resulting in high release of matrix-degrading matrix metalloproteinase 9 (MMP9). In agreement, therapeutic disturbance of this process using Src tyrosine kinase inhibitors impaired proangiogenic capacity of such neutrophils. Similarly, inhibition of MMP9 activity resulted in significant impairment of neutrophil-mediated angiogenesis. All in all, deficiency in TGF-β/ALK1/ENG signaling in HHT neutrophils results in their proangiogenic activation and disease progression. Therapeutic strategies targeting neutrophil degranulation and MMP9 release and activity may serve as a potential therapeutic option for HHT.

Keywords: ALK1; ENG; HHT; MMP9; angiogenesis; neutrophils.

MeSH terms

  • Activin Receptors, Type II / genetics
  • Activin Receptors, Type II / metabolism
  • Activin Receptors, Type II / therapeutic use
  • Endoglin / genetics
  • Endoglin / metabolism
  • Endothelial Cells / metabolism
  • Humans
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase 9 / therapeutic use
  • Neutrophils / metabolism
  • Signal Transduction / genetics
  • Telangiectasia, Hereditary Hemorrhagic* / drug therapy
  • Telangiectasia, Hereditary Hemorrhagic* / genetics
  • Transforming Growth Factor beta

Substances

  • Matrix Metalloproteinase 9
  • Endoglin
  • Activin Receptors, Type II
  • Transforming Growth Factor beta
  • ENG protein, human