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Published online January 14, 2008
doi:10.1083/jcb.200706072
The Journal of Cell Biology, Vol. 180, No. 1, 101-112
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Schleicher et al.
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Article

 Prohibitin-1 maintains the angiogenic capacity of endothelial cells by regulating mitochondrial function and senescence

Michael Schleicher1, Benjamin R. Shepherd2, Yajaira Suarez1,2, Carlos Fernandez-Hernando1, Jun Yu1, Yong Pan3,4, Lisette M. Acevedo1, Gerald S. Shadel3, and William C. Sessa1

1 Department of Pharmacology, and Vascular Biology and Therapeutics Program, 2 Department of Immunobiology, and 3 Department of Pathology, Yale University School of Medicine, New Haven, CT 06536
4 Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520

Correspondence to W. Sessa: william.sessa{at}yale.edu

Prohibitin 1 (PHB1) is a highly conserved protein that is mainly localized to the inner mitochondrial membrane and has been implicated in regulating mitochondrial function in yeast. Because mitochondria are emerging as an important regulator of vascular homeostasis, we examined PHB1 function in endothelial cells. PHB1 is highly expressed in the vascular system and knockdown of PHB1 in endothelial cells increases mitochondrial production of reactive oxygen species via inhibition of complex I, which results in cellular senescence. As a direct consequence, both Akt and Rac1 are hyperactivated, leading to cytoskeletal rearrangements and decreased endothelial cell motility, e.g., migration and tube formation. This is also reflected in an in vivo angiogenesis assay, where silencing of PHB1 blocks the formation of functional blood vessels. Collectively, our results provide evidence that PHB1 is important for mitochondrial function and prevents reactive oxygen species–induced senescence and thereby maintains the angiogenic capacity of endothelial cells.

Abbreviations used in this paper: BAEC, bovine aortic endothelial cell; EC, endothelial cell; HUVEC, human umbilical vein EC; PAK, p21-activated kinase; PECAM-1, platelet EC adhesion molecule 1; PEG, polyethylene glycol; PHB1, prohibitin-1; PI3-K, phosphatidyl inositol 3-kinase; ROS, reactive oxygen species; SMC, smooth muscle cell.


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