Endothelial RhoA GTPase is essential for in vitro endothelial functions but dispensable for physiological in vivo angiogenesis

Sci Rep. 2019 Aug 12;9(1):11666. doi: 10.1038/s41598-019-48053-z.

Abstract

Imbalanced angiogenesis is a characteristic of several diseases. Rho GTPases regulate multiple cellular processes, such as cytoskeletal rearrangement, cell movement, microtubule dynamics, signal transduction and gene expression. Among the Rho GTPases, RhoA, Rac1 and Cdc42 are best characterized. The role of endothelial Rac1 and Cdc42 in embryonic development and retinal angiogenesis has been studied, however the role of endothelial RhoA is yet to be explored. Here, we aimed to identify the role of endothelial RhoA in endothelial cell functions, in embryonic and retinal development and explored compensatory mechanisms. In vitro, RhoA is involved in cell proliferation, migration and tube formation, triggered by the angiogenesis inducers Vascular Endothelial Growth Factor (VEGF) and Sphingosine-1 Phosphate (S1P). In vivo, through constitutive and inducible endothelial RhoA deficiency we tested the role of endothelial RhoA in embryonic development and retinal angiogenesis. Constitutive endothelial RhoA deficiency, although decreased survival, was not detrimental for embryonic development, while inducible endothelial RhoA deficiency presented only mild deficiencies in the retina. The redundant role of RhoA in vivo can be attributed to potential differences in the signaling cues regulating angiogenesis in physiological versus pathological conditions and to the alternative compensatory mechanisms that may be present in the in vivo setting.

Publication types

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

MeSH terms

  • Animals
  • Cell Line
  • Cell Movement
  • Cell Proliferation
  • Embryo, Mammalian
  • Embryonic Development
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Female
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lysophospholipids / metabolism
  • Male
  • Mice, Transgenic
  • Neovascularization, Physiologic*
  • Retinal Vessels / embryology
  • Retinal Vessels / metabolism
  • Signal Transduction / physiology
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Vascular Endothelial Growth Factor A / metabolism
  • rhoA GTP-Binding Protein / deficiency*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*

Substances

  • Lysophospholipids
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • RHOA protein, human
  • sphingosine 1-phosphate
  • RhoA protein, mouse
  • rhoA GTP-Binding Protein
  • Sphingosine