Inhibition of Rho-dependent kinases ROCK I/II activates VEGF-driven retinal neovascularization and sprouting angiogenesis.

Abstract

Vascular endothelial growth factor (VEGF) is an endothelial-specific growth factor that activates the small GTPase RhoA. While the role of RhoA for VEGF-driven endothelial migration and angiogenesis has been studied in detail, the function of its target proteins, the Rho-dependent kinases ROCK I and II, are controversially discussed. Using the mouse model of oxygen-induced proliferative retinopathy, ROCK I/II inhibition by H-1152 resulted in increased angiogenesis. This enhanced angiogenesis, however, was completely blocked by the VEGF-receptor antagonist PTK787/ZK222584. Loss-of-function experiments in endothelial cells revealed that inhibition of ROCK I/II using the pharmacological inhibitor H-1152 and ROCK I/II-specific small-interfering RNAs resulted in a rise of VEGF-driven sprouting angiogenesis. These functional data were biochemically substantiated by showing an enhanced VEGF-receptor kinase insert domain receptor phosphorylation and extracellular signal-regulated kinase 1/2 activation after inhibition of ROCK I/II. Thus our data identify that the inhibition of Rho-dependent kinases ROCK I/II activates angiogenesis both, in vitro and in vivo.

• Authors: Jens Kroll, Daniel Epting, Katrin Kern, Christian T Dietz, Yuxi Feng, Hans-Peter Hammes, Thomas Wieland, Hellmut G Augustin
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 296 Issue 3 Pg. H893-9 (Mar 2009) ISSN: 0363-6135 [Print] United States
• PMID: 19181962 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine
• Angiogenesis Inducing Agents
• Angiogenesis Inhibitors
• Phthalazines
• Protein Kinase Inhibitors
• Pyridines
• RNA, Small Interfering
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• vascular endothelial growth factor A, mouse
• vatalanib
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• Receptors, Vascular Endothelial Growth Factor
• ROCK1 protein, human
• ROCK2 protein, human
• Rock1 protein, mouse
• Rock2 protein, mouse
• rho-Associated Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Oxygen

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• Angiogenesis Inducing Agents (pharmacology)
• Angiogenesis Inhibitors (pharmacology)
• Animals
• Animals, Newborn
• Cells, Cultured
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, enzymology)
• Humans
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Neovascularization, Physiologic (drug effects)
• Oxygen
• Phthalazines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyridines (pharmacology)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors, metabolism)
• Retinal Neovascularization (chemically induced, enzymology, physiopathology)
• Vascular Endothelial Growth Factor A (metabolism)
• rho-Associated Kinases (antagonists & inhibitors, genetics, metabolism)