Atheroprone fluid shear stress-regulated ALK1-Endoglin-SMAD signaling originates from early endosomes.

Autor: Mendez PL; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany.; Max Planck Institute for Molecular Genetics, Berlin, Germany.; International Max-Planck Research School for Biology and Computation, Berlin, Germany., Obendorf L; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany., Jatzlau J; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany., Burdzinski W; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany.; Berlin School for Regenerative Therapies, Berlin, Germany., Reichenbach M; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany., Nageswaran V; Charité-Universitätsmedizin Berlin, Klinik für Kardiologie, Campus Benjamin Franklin, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany., Haghikia A; Charité-Universitätsmedizin Berlin, Klinik für Kardiologie, Campus Benjamin Franklin, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.; Charité-Universitätsmedizin Berlin, Medizinische Klinik für Kardiologie und Angiologie, Campus Mitte, Berlin, Germany., Stangl V; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.; Berlin Institute of Health (BIH), Berlin, Germany., Hiepen C; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany.; Faculty of Engineering and Natural Sciences, Westphalian University of Applied Sciences, Recklinghausen, Germany., Knaus P; Freie Universität Berlin, Institute for Chemistry and Biochemistry, Berlin, Germany. petra.knaus@fu-berlin.de.; International Max-Planck Research School for Biology and Computation, Berlin, Germany. petra.knaus@fu-berlin.de.; Berlin School for Regenerative Therapies, Berlin, Germany. petra.knaus@fu-berlin.de.
Jazyk: angličtina
Zdroj: BMC biology [BMC Biol] 2022 Sep 28; Vol. 20 (1), pp. 210. Date of Electronic Publication: 2022 Sep 28.
DOI: 10.1186/s12915-022-01396-y
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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