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Vascular Biology

Calpains Contribute to Vascular Repair in Rapidly Progressive Form of Glomerulonephritis: Potential Role of Their Externalization

Béatrice Letavernier, Lara Zafrani, Dany Nassar, Joëlle Perez, Charlène Levi, Agnès Bellocq, Laurent Mesnard, Emmanuelle Sachon, Jean-Philippe Haymann, Selim Aractingi, Anne-Marie Faussat, Laurent Baud, Emmanuel Letavernier
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https://doi.org/10.1161/ATVBAHA.111.240242
Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;ATVBAHA.111.240242
Originally published November 17, 2011
Béatrice Letavernier
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Lara Zafrani
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Dany Nassar
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Joëlle Perez
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Charlène Levi
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Agnès Bellocq
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Laurent Mesnard
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Emmanuelle Sachon
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Jean-Philippe Haymann
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Selim Aractingi
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Anne-Marie Faussat
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Laurent Baud
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Emmanuel Letavernier
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Abstract

Objective—Calpains, calcium-activated proteases, mediate the angiogenic signals of vascular endothelial growth factor. However, their involvement in vascular repair has not been investigated and the underlying mechanisms remain to be fully elucidated.

Methods and Results—A rapidly progressive form of glomerulonephritis in wild type and transgenic mice expressing high levels of calpastatin, a calpain-specific inhibitor, was studied. Calpastatin transgene expression prevented the repair of peritubular capillaries and the recovery of renal function, limiting mouse survival. In vitro analysis detected a significant reduction of both intracellular and extracellular calpain activities in transgene expressing cells, whereas Western blotting revealed that proangiogenic factors vascular endothelial growth factor and norepinephrine increased calpain exteriorization. In vitro, extracellular calpains increased endothelial cell proliferation, migration and capillary tube formation. In vivo, delivery of nonpermeable extracellular calpastatin was sufficient to blunt angiogenesis and vascular repair. Endothelial cell response to extracellular calpains was associated with fibronectin cleavage, generating fibronectin fragments with proangiogenic capacity. In vivo, fibronectin cleavage was limited in the kidney of calpastatin transgenic mice with nephritis.

Conclusion—This study demonstrates that externalized calpains participate in angiogenesis and vascular repair, partly by promoting fibronectin cleavage and thereby amplifying vascular endothelial growth factor efficiency. Thus, manipulation of calpain externalization may have therapeutic implications to control angiogenesis.

  • angiogenesis
  • kidney
  • pathology
  • vascular biology
  • Received May 19, 2011.
  • Accepted November 2, 2011.
  • © 2011 American Heart Association, Inc.
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    Calpains Contribute to Vascular Repair in Rapidly Progressive Form of Glomerulonephritis: Potential Role of Their Externalization
    Béatrice Letavernier, Lara Zafrani, Dany Nassar, Joëlle Perez, Charlène Levi, Agnès Bellocq, Laurent Mesnard, Emmanuelle Sachon, Jean-Philippe Haymann, Selim Aractingi, Anne-Marie Faussat, Laurent Baud and Emmanuel Letavernier
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;ATVBAHA.111.240242, originally published November 17, 2011
    https://doi.org/10.1161/ATVBAHA.111.240242

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    Calpains Contribute to Vascular Repair in Rapidly Progressive Form of Glomerulonephritis: Potential Role of Their Externalization
    Béatrice Letavernier, Lara Zafrani, Dany Nassar, Joëlle Perez, Charlène Levi, Agnès Bellocq, Laurent Mesnard, Emmanuelle Sachon, Jean-Philippe Haymann, Selim Aractingi, Anne-Marie Faussat, Laurent Baud and Emmanuel Letavernier
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;ATVBAHA.111.240242, originally published November 17, 2011
    https://doi.org/10.1161/ATVBAHA.111.240242
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