title: Girdin/GIV regulates transendothelial permeability by controlling VE-cadherin trafficking through the small GTPase, R-Ras.
abstract: Vascular permeability is regulated by intercellular junction organization of endothelial cells, the dysfunction of which is implicated in numerous pathological conditions. Molecular mechanisms of how endothelial cells regulate intercellular junction in response to extracellular signals, however, have so far remained elusive. This study identified that Girdin (also termed GIV), an Akt substrate functioning in post natal angiogenesis, was expressed in a mature endothelial monolayer, where it regulated VE-cadherin trafficking to maintain vascular integrity. Girdin depletion abrogated VEGF-induced VE-cadherin endocytosis and the disassembly of adherens junctions in a monolayer of endothelial cells, thus leading to a significant decrease in the permeability. We also showed that activated R-Ras, a member of the Ras family GTPase, known to be a master regulator of transendothelial permeability, interacts with Girdin, and facilitates the complex formation between Girdin and VE-cadherin in endothelial cells. However, the increased permeability mediated by the loss of R-Ras was rescued by Girdin depletion, thus suggesting that the interaction of Girdin with R-Ras functions in VE-cadherin trafficking pathways distinct from endocytosis. The recycling of VE-cadherin was promoted by the exogenous expression of the active mutant of R-Ras, which was attenuated in the Girdin-depleted endothelial cells. These results show that Girdin regulates transendothelial permeability in synergy with R-Ras and VE-cadherin in an endothelial monolayer.
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors: Hitoshi
authors: H
authors: Ichimiya
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: maedaken@med.nagoya-u.ac.jp.
authors: Kengo
authors: K
authors: Maeda
authors: Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors: Atsushi
authors: A
authors: Enomoto
authors: Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors: Liang
authors: L
authors: Weng
authors: Department of Pathology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors: Masahide
authors: M
authors: Takahashi
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors: Toyoaki
authors: T
authors: Murohara
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability; D042783:Endothelial Cells / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008840:Microfilament Proteins / Q000378:metabolism*; D021381:Protein Transport; D033921:Vesicular Transport Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D018631:ras Proteins; D000099152:Cadherin 5; C502451:CCDC88A protein, human; C085929:RRAS protein, human
keywords: Girdin; R-Ras; VE-cadherin; Vascular permeability