dc.contributor.author
Mendez, Paul-Lennard
dc.contributor.author
Obendorf, Leon
dc.contributor.author
Jatzlau, Jerome
dc.contributor.author
Burdzinski, Wiktor
dc.contributor.author
Reichenbach, Maria
dc.contributor.author
Nageswaran, Vanasa
dc.contributor.author
Haghikia, Arash
dc.contributor.author
Stangl, Verena
dc.contributor.author
Hiepen, Christian
dc.contributor.author
Knaus, Petra
dc.date.accessioned
2022-10-07T10:24:34Z
dc.date.available
2022-10-07T10:24:34Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/36512
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-36225
dc.description.abstract
Background
Fluid shear stress enhances endothelial SMAD1/5 signaling via the BMP9-bound ALK1 receptor complex supported by the co-receptor Endoglin. While moderate SMAD1/5 activation is required to maintain endothelial quiescence, excessive SMAD1/5 signaling promotes endothelial dysfunction. Increased BMP signaling participates in endothelial-to-mesenchymal transition and inflammation culminating in vascular diseases such as atherosclerosis. While the function of Endoglin has so far been described under picomolar concentrations of BMP9 and short-term shear application, we investigated Endoglin under physiological BMP9 and long-term pathophysiological shear conditions.
Results
We report here that knock-down of Endoglin leads to exacerbated SMAD1/5 phosphorylation and atheroprone gene expression profile in HUVECs sheared for 24 h. Making use of the ligand-trap ALK1-Fc, we furthermore show that this increase is dependent on BMP9/10. Mechanistically, we reveal that long-term exposure of ECs to low laminar shear stress leads to enhanced Endoglin expression and endocytosis of Endoglin in Caveolin-1-positive early endosomes. In these endosomes, we could localize the ALK1-Endoglin complex, labeled BMP9 as well as SMAD1, highlighting Caveolin-1 vesicles as a SMAD signaling compartment in cells exposed to low atheroprone laminar shear stress.
Conclusions
We identified Endoglin to be essential in preventing excessive activation of SMAD1/5 under physiological flow conditions and Caveolin-1-positive early endosomes as a new flow-regulated signaling compartment for BMP9-ALK1-Endoglin signaling axis in atheroprone flow conditions.
en
dc.format.extent
18 Seiten
dc.rights.uri
https://creativecommons.org/licenses/by/4.0/
dc.subject
Fluid shear stress
en
dc.subject
Endothelial cell
en
dc.subject
Atherosclerosis
en
dc.subject.ddc
500 Naturwissenschaften und Mathematik::540 Chemie::540 Chemie und zugeordnete Wissenschaften
dc.title
Atheroprone fluid shear stress-regulated ALK1-Endoglin-SMAD signaling originates from early endosomes
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation.articlenumber
210
dcterms.bibliographicCitation.doi
10.1186/s12915-022-01396-y
dcterms.bibliographicCitation.journaltitle
BMC Biology
dcterms.bibliographicCitation.volume
20
dcterms.bibliographicCitation.url
https://doi.org/10.1186/s12915-022-01396-y
refubium.affiliation
Biologie, Chemie, Pharmazie
refubium.affiliation.other
Institut für Chemie und Biochemie
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refubium.funding
Springer Nature DEAL
refubium.note.author
Die Publikation wurde aus Open Access Publikationsgeldern der Freien Universität Berlin gefördert.
refubium.resourceType.isindependentpub
no
dcterms.accessRights.openaire
open access
dcterms.isPartOf.eissn
1741-7007