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J Cell Sci. 2013 Dec 15;126(Pt 24):5541-52. doi: 10.1242/jcs.115972. Epub 2013 Sep 17.

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

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Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT 06520, USA.

Erratum in

  • J Cell Sci. 2014 May 1;127(Pt 9):2120.


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.


Cadherin 5; Cytoskeleton; Nitric oxide; Src; VE-cadherin; VEGF; eNOS

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