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F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling.

ABSTRACT: During immune surveillance and inflammation, leukocytes exit the vasculature through transient openings in the endothelium without causing plasma leakage. However, the exact mechanisms behind this intriguing phenomenon are still unknown. Here we report that maintenance of endothelial barrier integrity during leukocyte diapedesis requires local endothelial RhoA cycling. Endothelial RhoA depletion in vitro or Rho inhibition in vivo provokes neutrophil-induced vascular leakage that manifests during the physical movement of neutrophils through the endothelial layer. Local RhoA activation initiates the formation of contractile F-actin structures that surround emigrating neutrophils. These structures that surround neutrophil-induced endothelial pores prevent plasma leakage through actomyosin-based pore confinement. Mechanistically, we found that the initiation of RhoA activity involves ICAM-1 and the Rho GEFs Ect2 and LARG. In addition, regulation of actomyosin-based endothelial pore confinement involves ROCK2b, but not ROCK1. Thus, endothelial cells assemble RhoA-controlled contractile F-actin structures around endothelial pores that prevent vascular leakage during leukocyte extravasation.

SUBMITTER: Heemskerk N

PROVIDER: S-EPMC4737874 | biostudies-other | 2016

REPOSITORIES: biostudies-other

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F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling.

Heemskerk Niels N Schimmel Lilian L Oort Chantal C van Rijssel Jos J Yin Taofei T Ma Bin B van Unen Jakobus J Pitter Bettina B Huveneers Stephan S Goedhart Joachim J Wu Yi Y Montanez Eloi E Woodfin Abigail A van Buul Jaap D JD

Nature communications 20160127

During immune surveillance and inflammation, leukocytes exit the vasculature through transient openings in the endothelium without causing plasma leakage. However, the exact mechanisms behind this intriguing phenomenon are still unknown. Here we report that maintenance of endothelial barrier integrity during leukocyte diapedesis requires local endothelial RhoA cycling. Endothelial RhoA depletion in vitro or Rho inhibition in vivo provokes neutrophil-induced vascular leakage that manifests during ...[more]

PMID: 26814335

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Project description:The aim of this study was to evaluate the effect of local and systemic administration of antimicrobials to leukocyte- and platelet-rich fibrin (L-PRF). For part A, 16 tubes of venous blood were collected from each of eight systemically healthy subjects. Prior to blood centrifugation, 12 of the 16 tubes were injected with 0.125 ml, 0.25 ml or 0.50 ml metronidazole solution. One set of L-PRF membranes was used to assess the release of vascular endothelial growth factor AB, platelet-derived growth factor, transforming growth factor beta 1, and bone morphogenetic protein 2 at indicated time points. The metronidazole release over time by L-PRF membranes was also evaluated. The remaining L-PRF membranes were placed on the surface of agar plates inoculated with three different periodontal pathogens to determine their antibacterial activity. For part B, another six subjects were enrolled with three subjects taking 2 g amoxicillin and three subjects 500 mg metronidazole as prophylaxis prior to a periodontal treatment. Before and 2 h after consuming one of the prescribed antimicrobials, three tubes of blood were collected for preparing L-PRF membranes. These membranes were used to measure the antibacterial activity against periodontal pathogens. No statistically significant difference could be found in the release of growth factors between L-PRF membranes with and without incorporation of metronidazole solution. The release of metronidazole could be detected up to day 3, however with the highest concentration during the first 4 h. This concentration was dose dependent. The antibacterial capacity of L-PRF membranes increased significantly for both the systemic intake, and after the addition of metronidazole solution to the blood tubes before centrifugation, the latter again dose dependent. The antibacterial capacity of L-PRF against the periodontal pathogens tested can significantly be enhanced by the addition of antimicrobials, without disadvantage for the release of growth factors.

Dataset Information

F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling.

Publications

F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling.

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