TY  - JOUR
A1  - Haarmann, Axel
A1  - Vollmuth, Christoph
A1  - Kollikowski, Alexander M.
A1  - Heuschmann, Peter U.
A1  - Pham, Mirko
A1  - Stoll, Guido
A1  - Neugebauer, Hermann
A1  - Schuhmann, Michael K.
T1  - Vasoactive soluble endoglin: a novel biomarker indicative of reperfusion after cerebral large-vessel occlusion
JF  - Cells
N2  - Now that mechanical thrombectomy has substantially improved outcomes after large-vessel occlusion stroke in up to every second patient, futile reperfusion wherein successful recanalization is not followed by a favorable outcome is moving into focus. Unfortunately, blood-based biomarkers, which identify critical stages of hemodynamically compromised yet reperfused tissue, are lacking. We recently reported that hypoxia induces the expression of endoglin, a TGF-β co-receptor, in human brain endothelium in vitro. Subsequent reoxygenation resulted in shedding. Our cell model suggests that soluble endoglin compromises the brain endothelial barrier function. To evaluate soluble endoglin as a potential biomarker of reperfusion (-injury) we analyzed its concentration in 148 blood samples of patients with acute stroke due to large-vessel occlusion. In line with our in vitro data, systemic soluble endoglin concentrations were significantly higher in patients with successful recanalization, whereas hypoxia alone did not induce local endoglin shedding, as analyzed by intra-arterial samples from hypoxic vasculature. In patients with reperfusion, higher concentrations of soluble endoglin additionally indicated larger infarct volumes at admission. In summary, we give translational evidence that the sequence of hypoxia and subsequent reoxygenation triggers the release of vasoactive soluble endoglin in large-vessel occlusion stroke and can serve as a biomarker for severe ischemia with ensuing recanalization/reperfusion.
KW  - endoglin
KW  - brain endothelium
KW  - stroke
KW  - shedding
KW  - mechanical thrombectomy
KW  - hypoxia
KW  - reperfusion injury
KW  - biomarker
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-304995
SN  - 2073-4409
VL  - 12
IS  - 2
ER  - 
TY  - JOUR
A1  - Koo, Chek Ziu
A1  - Matthews, Alexandra L.
A1  - Harrison, Neale
A1  - Szyroka, Justyna
A1  - Nieswandt, Bernhard
A1  - Gardiner, Elizabeth E.
A1  - Poulter, Natalie S.
A1  - Tomlinson, Michael G.
T1  - The platelet collagen receptor GPVI is cleaved by Tspan15/ADAM10 and Tspan33/ADAM10 molecular scissors
JF  - International Journal of Molecular Sciences
N2  - The platelet-activating collagen receptor GPVI represents the focus of clinical trials as an antiplatelet target for arterial thrombosis, and soluble GPVI is a plasma biomarker for several human diseases. A disintegrin and metalloproteinase 10 (ADAM10) acts as a ‘molecular scissor’ that cleaves the extracellular region from GPVI and many other substrates. ADAM10 interacts with six regulatory tetraspanin membrane proteins, Tspan5, Tspan10, Tspan14, Tspan15, Tspan17 and Tspan33, which are collectively termed the TspanC8s. These are emerging as regulators of ADAM10 substrate specificity. Human platelets express Tspan14, Tspan15 and Tspan33, but which of these regulates GPVI cleavage remains unknown. To address this, CRISPR/Cas9 knockout human cell lines were generated to show that Tspan15 and Tspan33 enact compensatory roles in GPVI cleavage, with Tspan15 bearing the more important role. To investigate this mechanism, a series of Tspan15 and GPVI mutant expression constructs were designed. The Tspan15 extracellular region was found to be critical in promoting GPVI cleavage, and appeared to achieve this by enabling ADAM10 to access the cleavage site at a particular distance above the membrane. These findings bear implications for the regulation of cleavage of other ADAM10 substrates, and provide new insights into post-translational regulation of the clinically relevant GPVI protein.
KW  - ADAM10
KW  - GPVI
KW  - tetraspanin
KW  - platelet
KW  - shedding
KW  - TspanC8
KW  - metalloproteinase
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284468
SN  - 1422-0067
VL  - 23
IS  - 5
ER  -