Chergova 2015 Abstract MiPschool London 2015

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Role of the mitochondrial fission factor DRP1 in angiogenesis.

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Hoitzing H, Johnston IG, Jones NS (2015)

Event: MiPschool London 2015

Angiogenesis is the process of new blood vessel formation from preexisting vasculature [1]. Endothelial cells (ECs) are responsible for the development of the vascular plexus. This process is very active during embryonic development whereas ECs are quiescent during adulthood. Reactivation of angiogenesis is related to various pathological states such as tumor growth. Angiogenesis requires remodeling and new tissue formation and therefore a higher demand in ATP. Mitochondria are essential cell organelles with pivotal role in processes of life and death and they are the main source of ATP in the cell. Nevertheless, it has been shown that VEGF, a key pro-angiogenic factor, is involved in mitochondrial biogenesis [2]. However, the role of mitochondria in the endothelium is poorly understood. Mitochondria are extremely dynamic structures. Their morphology is modulated through processes of fusion and fission in order to fulfill their diverse functions [3]. Mitochondrial morphology is orchestrated by a number of dynamin-like GTPases. Mitochondrial fusion depends on mitofusin 1 (MFN1), mitofusin 2 (MFN2) and Optic Atrophy 1 (OPA1). DRP1 is the key regulator of mitochondrial fission. The emerging of mitochondrial function in diverse cellular processes provoked our interest to study mitochondrial dynamics and the role of DRP1 in endothelial cells during angiogenesis.

In vitro we are approaching DRP1’s function in HUVEC cells (Human Umbilical Cord Endothelial Cells) under angiogenic stimulation or ablation. In vivo we will evaluate physiological angiogenesis using the mouse retinal neovascularization model [4] in the conditional endothelial knock out for DRP1.

Our results show that VEGF treatment of HUVECs decreases DRP1 levels. Parallel to this inhibition of angiogenesis by the anti-angiogenic factor 16K prolactin causes an increase of DRP1 expression. Furthermore, we evaluated angiogenesis by measuring cell migration, proliferation and permeability in HUVECs with down-regulation of DRP1 (siRNAs) and we observed an upregulation of angiogenic parameters.

Our preliminary data are suggesting a key role of mitochondrial dynamics in angiogenesis and a new function for DRP1 in endothelial cells. Our goal is to identify how pro and anti-angiogenic agents affect DRP1 and which are the molecular pathways through which DRP1 is affecting angiogenesis.

Keywords: Angiogenesis


Labels: MiParea: mt-Biogenesis;mt-density 


Organism: Human, Mouse  Tissue;cell: Endothelial;epithelial;mesothelial cell, HUVEC 





Affiliations

1-Dulbecco-Telethon Inst, Venetian Inst Mol Med, Padova, Italy

2-Dept Biol, Univ Padova, Italy. - m.chergova@gmail.com

3-Lab Mol Angiogenesis, GIGA-Cancer, Univ Liege, Belgium

References

  1. Risau W (1997) Mechanisms of angiogenesis. Nature 386:671‑4
  2. Wright GL, Maroulakou IG, Eldridge J, Liby TL, Sridharan V, Tsichlis PN, Muise-Helmericks RC (2008) VEGF stimulation of mitochondrial biogenesis: requirement of AKT3 kinase. FASEB J 22:3264-75.
  3. Corrado M, Scorrano L, Campello S (2012) Mitochondrial dynamics in cancer and neurodegenerative and neuroinflammatory diseases. Int J Cell Biol ID729290:13p.
  4. Stahl A, Connor KM, Sapieha P, Chen J, Dennison RJ, Krah NM, Seaward MR, Willett KL, Aderman CM, Guerin KI, Hua J, Löfqvist C, Hellström A, Smith LE (2010) The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci 51:2813-26