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- Title
RhoA/ROCK signaling is essential for multiple aspects of VEGF-mediated angiogenesis.
- Authors
Bryan, Brad A.; Dennstedt, Emily; Mitchell, Dianne C.; Walshe, Tony E.; Noma, Kensuke; Loureiro, Robyn; Saint-Geniez, Magali; Campaigniac, Jean-Paul; Liao, James K.; D'Amore, Patricia A.
- Abstract
The small GTPase RhoA and its downstream effectors, ROCK1 and ROCK2, regulate a number of cellular processes, including cell motility, proliferation, survival, and permeability. Pharmacological inhibitors of the Rho pathway reportedly block angiogenesis; however, the molecular details of this inhibition are largely unknown. We demonstrate that vascular endothelial growth factor-A (VEGF) rapidly induces RhoA activation in endothelial cells (ECs). Moreover, the pharmacological inhibition of ROCK1/2 using 10µM Y-27632 (the IC50 for this compound in ECs) strongly disrupts vasculogenesis in pluripotent embryonic stem cell cultures, VEGF-mediated regenerative angiogenesis in ex vivo retinal explants, and VEGF-mediated in vitro EC tube formation. Furthermore, using small interfering RNA knockdown and mouse heterozygote knockouts of ROCK1 and ROCK2, we provide data indicating that VEGF-driven angiogenesis is largely mediated through ROCK2. These data demonstrate that Rho/ ROCK signaling is an important mediator in a number of angiogenic processes, including EC migration, survival, and cell permeability, and suggest that Rho/ROCK inhibition may prove useful for the treatment of angiogenesis-related disorders.
- Subjects
CELLULAR control mechanisms; CELL motility; CELL proliferation; VASCULAR endothelial growth factors; GUANOSINE triphosphatase
- Publication
FASEB Journal, 2010, Vol 24, Issue 9, p3186
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.09-145102