Mitofusins are required for angiogenic function and modulate different signaling pathways in cultured endothelial cells

J Mol Cell Cardiol. 2011 Dec;51(6):885-93. doi: 10.1016/j.yjmcc.2011.07.023. Epub 2011 Aug 2.


The mitofusin proteins MFN1 and MFN2 function to maintain mitochondrial networks by binding one another and initiating outer mitochondrial membrane fusion. While it has recently been recognized that vascular endothelial cells rely upon mitochondria as signaling rather than energy-producing moieties, the role of mitochondrial dynamics in endothelial cell function has not been addressed. To begin to understand what role mitochondrial dynamics play in this context, we examined the regulation of MFN1 and MFN2 and the consequences of siRNA-mediated knockdown of these proteins in cultured endothelial cells. Treatment with VEGF-A led to the upregulation of MFN2 and, to a lesser extent, MFN1. Knockdown of either MFN led to disrupted mitochondrial networks and diminished mitochondrial membrane potential. Knockdown of either MFN decreased VEGF-mediated migration and differentiation into network structures. MFN ablation also diminished endothelial cell viability and increased apoptosis under low mitogen conditions. Knockdown of MFN2 uniquely resulted in a decrease in the generation of reactive oxygen species as well as the blunting of the gene expression of components of the respiratory chain and transcription factors associated with oxidative metabolism. In contrast, ablation of MFN1 led to the selective reduction of VEGF-stimulated Akt-eNOS signaling. Taken together, our data indicate that mitochondrial dynamics, particularly those mediated by the mitofusins, play a role in endothelial cell function and viability.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Survival / genetics
  • Cells, Cultured
  • Endothelial Cells / metabolism*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • Gene Expression
  • Gene Expression Regulation
  • Gene Knockdown Techniques
  • Humans
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondrial Membrane Transport Proteins / genetics
  • Mitochondrial Membrane Transport Proteins / metabolism*
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • Neovascularization, Physiologic*
  • Signal Transduction*
  • Stress, Physiological
  • Vascular Endothelial Growth Factor A / metabolism


  • Mitochondrial Membrane Transport Proteins
  • Mitochondrial Proteins
  • Vascular Endothelial Growth Factor A
  • GTP Phosphohydrolases
  • MFN2 protein, human
  • Mfn1 protein, human