Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor.
Endothelial secretion of von Willebrand factor (VWF) from intracellular organelles known as Weibel-Palade bodies (WPBs) is required for platelet adhesion to the injured vessel wall. Here we demonstrate that WPBs are often found near or within autophagosomes and that endothelial autophagosomes contain abundant VWF protein. Pharmacological inhibitors of autophagy or knockdown of the essential autophagy genes Atg5 or Atg7 inhibits the in vitro secretion of VWF. Furthermore, although mice with endothelial-specific deletion of Atg7 have normal vessel architecture and capillary density, they exhibit impaired epinephrine-stimulated VWF release, reduced levels of high-molecular weight VWF multimers and a corresponding prolongation of bleeding times. Endothelial-specific deletion of Atg5 or pharmacological inhibition of autophagic flux results in a similar in vivo alteration of hemostasis. Thus, autophagy regulates endothelial VWF secretion, and transient pharmacological inhibition of autophagic flux may be a useful strategy to prevent thrombotic events.
1] Center for Molecular Medicine, National Heart, Lung and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, USA. [2].
Takehiro
T
Torisu
Kumiko
K
Torisu
In Hye
IH
Lee
Jie
J
Liu
Daniela
D
Malide
Christian A
CA
Combs
Xufeng S
XS
Wu
Ilsa I
II
Rovira
Maria M
MM
Fergusson
Roberto
R
Weigert
Patricia S
PS
Connelly
Mathew P
MP
Daniels
Masaaki
M
Komatsu
Liu
L
Cao
Toren
T
Finkel
D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071193:Autophagy-Related Protein 7; D042783:Endothelial Cells / Q000378:metabolism*; D005089:Exocytosis; D006487:Hemostasis; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics; D020302:Weibel-Palade Bodies / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism*
C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins; D014841:von Willebrand Factor; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes