TY - JOUR
T1 - F-actin-rich contractile endothelial pores prevent vascular leakage during leukocyte diapedesis through local RhoA signalling
AU - Heemskerk, N.
AU - Schimmel, L.
AU - Oort, C.
AU - van Rijssel, J.
AU - Yin, T.
AU - Ma, B.
AU - van Unen, J.
AU - Pitter, B.
AU - Huveneers, S.
AU - Goedhart, J.
AU - Wu, Y.
AU - Montanez, E.
AU - Woodfin, A.
AU - van Buul, J.D.
N1 - With suppelementary information
PY - 2016/1/27
Y1 - 2016/1/27
N2 - 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.
AB - 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.
UR - https://pure.uva.nl/ws/files/2721482/175414_F_actin_rich_contractile_endothelial_pores_suppl._1.pdf
UR - https://pure.uva.nl/ws/files/2721484/175415_F_actin_rich_contractile_endothelial_pores_suppl._2.mov
UR - https://pure.uva.nl/ws/files/2721486/175416_F_actin_rich_contractile_endothelial_pores_suppl._3.mov
UR - https://pure.uva.nl/ws/files/2721488/175417_F_actin_rich_contractile_endothelial_pores_suppl._4.mov
UR - https://pure.uva.nl/ws/files/2721490/175418_F_actin_rich_contractile_endothelial_pores_suppl._5.mov
UR - https://pure.uva.nl/ws/files/2721492/175419_F_actin_rich_contractile_endothelial_pores_suppl._6.mov
UR - https://pure.uva.nl/ws/files/2721494/175420_F_actin_rich_contractile_endothelial_pores_suppl._7.mov
UR - https://pure.uva.nl/ws/files/2721496/175421_F_actin_rich_contractile_endothelial_pores_suppl._8.mov
UR - https://pure.uva.nl/ws/files/2721498/175422_F_actin_rich_contractile_endothelial_pores_suppl._9.mov
UR - https://pure.uva.nl/ws/files/2721500/175423_F_actin_rich_contractile_endothelial_pores_suppl._10.mov
UR - https://pure.uva.nl/ws/files/2721502/175424_F_actin_rich_contractile_endothelial_pores_suppl._11.mov
U2 - https://doi.org/10.1038/ncomms10493
DO - https://doi.org/10.1038/ncomms10493
M3 - Article
C2 - 26814335
SN - 2041-1723
VL - 7
SP - 10493
JO - Nature communications
JF - Nature communications
M1 - 10493
ER -