eNOS-derived nitric oxide regulates endothelial barrier function through VE-cadherin and Rho GTPases.

Abstract

Transient disruption of endothelial adherens junctions and cytoskeletal remodeling are responsible for increases in vascular permeability induced by inflammatory stimuli and vascular endothelial growth factor (VEGF). Nitric oxide (NO) produced by endothelial NO synthase (eNOS) is crucial for VEGF-induced changes in permeability in vivo; however, the molecular mechanism by which endogenous NO modulates endothelial permeability is not clear. Here, we show that the lack of eNOS reduces VEGF-induced permeability, an effect mediated by enhanced activation of the Rac GTPase and stabilization of cortical actin. The loss of NO increased the recruitment of the Rac guanine-nucleotide-exchange factor (GEF) TIAM1 to adherens junctions and VE-cadherin (also known as cadherin 5), and reduced Rho activation and stress fiber formation. In addition, NO deficiency reduced VEGF-induced VE-cadherin phosphorylation and impaired the localization, but not the activation, of c-Src to cell junctions. The physiological role of eNOS activation is clear given that VEGF-, histamine- and inflammation-induced vascular permeability is reduced in mice bearing a non-phosphorylatable knock-in mutation of the key eNOS phosphorylation site S1176. Thus, NO is crucial for Rho GTPase-dependent regulation of cytoskeletal architecture leading to reversible changes in vascular permeability.

• Authors: Annarita Di Lorenzo, Michelle I Lin, Takahisa Murata, Shira Landskroner-Eiger, Michael Schleicher, Milankumar Kothiya, Yasuko Iwakiri, Jun Yu, Paul L Huang, William C Sessa
• Journal: Journal of cell science (J Cell Sci) Vol. 126 Issue Pt 24 Pg. 5541-52 (Dec 15 2013) ISSN: 1477-9137 [Electronic] England
• PMID: 24046447 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Cadherins
• Guanine Nucleotide Exchange Factors
• T-Lymphoma Invasion and Metastasis-inducing Protein 1
• TIAM1 protein, human
• Vascular Endothelial Growth Factor A
• cadherin 5
• Nitric Oxide
• NOS3 protein, human
• Nitric Oxide Synthase Type III
• CSK Tyrosine-Protein Kinase
• src-Family Kinases
• CSK protein, human

Topics

• Adherens Junctions (metabolism)
• Animals
• Antigens, CD (metabolism)
• CSK Tyrosine-Protein Kinase
• Cadherins (metabolism)
• Capillary Permeability
• Cells, Cultured
• Endothelial Cells (enzymology)
• Endothelium, Vascular (cytology, metabolism)
• Guanine Nucleotide Exchange Factors (metabolism)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide (physiology)
• Nitric Oxide Synthase Type III (genetics, metabolism)
• Phosphorylation
• Protein Processing, Post-Translational
• Protein Transport
• Stress Fibers (metabolism)
• T-Lymphoma Invasion and Metastasis-inducing Protein 1
• Vascular Endothelial Growth Factor A (physiology)
• src-Family Kinases (metabolism)