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

Autor: Paul-Lennard Mendez, Leon Obendorf, Jerome Jatzlau, Wiktor Burdzinski, Maria Reichenbach, Vanasa Nageswaran, Arash Haghikia, Verena Stangl, Christian Hiepen, Petra Knaus
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: BMC Biology, Vol 20, Iss 1, Pp 1-18 (2022)
Druh dokumentu: article
ISSN: 1741-7007
DOI: 10.1186/s12915-022-01396-y
Popis: 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.
Databáze: Directory of Open Access Journals
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