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@ARTICLE{Duerig:278369,
author = {I. Duerig and E. Pylaeva and I. Ozel and S. Weinwright and
I. Thiel and S. Bordbari and M. Domnich and E. Siakaeva and
A. Lakomek and F. Toppe and C. Schleupner and U. Geisthoff
and S. Lang$^*$ and F. Droege and J. Jablonska$^*$},
title = {{N}on-functional {TGF}-β/{ALK}1/{ENG} {S}ignaling
{P}athway supports neutrophil pro-angiogenic activity in
{H}ereditary {H}emorrhagic {T}elangiectasia},
journal = {Journal of leukocyte biology},
volume = {114},
number = {6},
issn = {0741-5400},
address = {Hoboken, NJ},
publisher = {Wiley},
reportid = {DKFZ-2023-01619},
pages = {639-650},
year = {2023},
note = {2023 Nov 24;114(6):639-650},
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.},
cin = {ED01},
ddc = {570},
cid = {I:(DE-He78)ED01-20160331},
pnm = {899 - ohne Topic (POF4-899)},
pid = {G:(DE-HGF)POF4-899},
typ = {PUB:(DE-HGF)16},
doi = {10.1093/jleuko/qiad090},
url = {https://inrepo02.dkfz.de/record/278369},
}