Journal Article

DKFZ-2023-01619

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Non-functional TGF-β/ALK1/ENG Signaling Pathway supports neutrophil pro-angiogenic activity in Hereditary Hemorrhagic Telangiectasia

Duerig, I. ; Pylaeva, E. ; Ozel, I. ; Weinwright, S. ; Thiel, I. ; Bordbari, S. ; Domnich, M. ; Siakaeva, E. ; Lakomek, A. ; Toppe, F. ; Schleupner, C. ; Geisthoff, U. ; Lang, S.DKFZ* ; Droege, F. ; Jablonska, J.DKFZ*

2023
Wiley Hoboken, NJ

This record in other databases:

Please use a persistent id in citations: doi:10.1093/jleuko/qiad090

Abstract: 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 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.

Note: 2023 Nov 24;114(6):639-650

---

Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

---

Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Wiley ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---