Evidence map›Paper›PMID 35477279›Full record

ArticleArteriosclerosis, thrombosis, and vascular biology2022

DOCK4 Regulation of Rho GTPases Mediates Pulmonary Vascular Barrier Function.

Pascal Yazbeck, Xavier Cullere, Paul Bennett, Vijay Yajnik, Huan Wang, Kenji Kawada, Vanessa M Davis, Asit Parikh, Andrew Kuo, Vijayashree Mysore and 3 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Arteriosclerosis, thrombosis, and vascular biology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
0.8field-weighted citation impact, top 34% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed, 8 citations in OpenAlex.

  1. Review
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors at 3 institutions in 2 countries.

Pascal Yazbeck *Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (P.Y., F.C., P.B., H.W., V.M.D., V.M., D.S.M., T.N.M.).
Xavier Cullere *Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (P.Y., F.C., P.B., H.W., V.M.D., V.M., D.S.M., T.N.M.).
Paul BennettDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (P.Y., F.C., P.B., H.W., V.M.D., V.M., D.S.M., T.N.M.).
Vijay YajnikDepartment of Medicine, Massachusetts General Hospital, Boston (V.Y., K.K., A.P.).
Huan WangDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (P.Y., F.C., P.B., H.W., V.M.D., V.M., D.S.M., T.N.M.).
Kenji KawadaDepartment of Medicine, Massachusetts General Hospital, Boston (V.Y., K.K., A.P.).
Vanessa M DavisDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (P.Y., F.C., P.B., H.W., V.M.D., V.M., D.S.M., T.N.M.).
Asit ParikhDepartment of Medicine, Massachusetts General Hospital, Boston (V.Y., K.K., A.P.).
Andrew KuoVascular Biology Program, Department of Surgery' Boston Children's Hospital and Harvard Medical School, MA (A.K., T.H.).
Vijayashree MysoreDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (P.Y., F.C., P.B., H.W., V.M.D., V.M., D.S.M., T.N.M.).
Timothy HlaVascular Biology Program, Department of Surgery' Boston Children's Hospital and Harvard Medical School, MA (A.K., T.H.).ORCID 0000-0001-8355-4065
David S MilstoneDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (P.Y., F.C., P.B., H.W., V.M.D., V.M., D.S.M., T.N.M.).
Tanya N MayadasDepartment of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA (P.Y., F.C., P.B., H.W., V.M.D., V.M., D.S.M., T.N.M.).ORCID 0000-0003-4143-3278
Brigham and Women's Hospital · USMassachusetts General Hospital · USBoston Children's Hospital · US

Funding

The Harvard Clinical and Translational Science CenterUL1TR002541 · NCATS · HARVARD MEDICAL SCHOOL · PI NADLER, LEE MARSHALL · 2018 to 2022
$93.0M
VCAM-1 IN CHRONIC INFLAMMATORY AND IMMUNE PROCESSESP01HL036028 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI MILSTONE, DAVID S · 1985 to 2013
$32.1M
Regulators of Immune Complex Mediated Neutrophil Recruitment and Tissue InjuryR01HL065095 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI MAYADAS, TANYA N · 1999 to 2025
$11.9M
Mechanisms of sphingolipid signaling in vascular health and diseaseR35HL135821 · NHLBI · BOSTON CHILDREN'S HOSPITAL · PI HLA, TIMOTHY TUN · 2017 to 2023
$6.3M
G protein-coupled receptor regulation of transcriptional mechanisms in the retinal vasculature.R01EY031715 · NEI · BOSTON CHILDREN'S HOSPITAL · PI HLA, TIMOTHY TUN · 2021 to 2025
$2.4M
TNFR2 Regulation of Leukocyte Recruitment in GlomerulonephritisR01DK099507 · NIDDK · BRIGHAM AND WOMEN'S HOSPITAL · PI MAYADAS, TANYA N · 2014 to 2018
$2.1M
PPARg in trophoblast and placental developmentR01HD040895 · NICHD · BRIGHAM AND WOMEN'S HOSPITAL · PI MILSTONE, DAVID S · 2003 to 2007
$1.5M
DOCK4 regulation of small GTPases in vascular permeabilityK01AR054984 · NIAMS · BRIGHAM AND WOMEN'S HOSPITAL · PI CULLERE, FRANCISCO · 2007 to 2011
$647k
NCATS NIH HHS UL1 TR002541NEI NIH HHS R01 EY031715NHLBI NIH HHS P01 HL036028NHLBI NIH HHS R01 HL065095NHLBI NIH HHS R35 HL135821NIAMS NIH HHS K01 AR054984NICHD NIH HHS R01 HD040895NIDDK NIH HHS R01 DK099507
6 · The paper itself

Abstract

backgroundThe vascular endothelium maintains tissue-fluid homeostasis by controlling the passage of large molecules and fluid between the blood and interstitial space. The interaction of catenins and the actin cytoskeleton with VE-cadherin (vascular endothelial cadherin) is the primary mechanism for stabilizing AJs (adherens junctions), thereby preventing lung vascular barrier disruption. Members of the Rho (Ras homology) family of GTPases and conventional GEFs (guanine exchange factors) of these GTPases have been demonstrated to play important roles in regulating endothelial permeability. Here, we evaluated the role of DOCK4 (dedicator of cytokinesis 4)-an unconventional Rho family GTPase GEF in vascular function.

methodsWe generated mice deficient in DOCK4' used DOCK4 silencing and reconstitution approaches in human pulmonary artery endothelial cells' used assays to evaluate protein localization, endothelial cell permeability, and small GTPase activation.

resultsOur data show that DOCK4-deficient mice are viable. However, these mice have hemorrhage selectively in the lung, incomplete smooth muscle cell coverage in pulmonary vessels, increased basal microvascular permeability, and impaired response to S1P (sphingosine-1-phosphate)-induced reversal of thrombin-induced permeability. Consistent with this, DOCK4 rapidly translocates to the cell periphery and associates with the detergent-insoluble fraction following S1P treatment, and its absence prevents S1P-induced Rac-1 activation and enhancement of barrier function. Moreover, DOCK4-silenced pulmonary artery endothelial cells exhibit enhanced basal permeability in vitro that is associated with enhanced Rho GTPase activation.

conclusionsOur findings indicate that DOCK4 maintains AJs necessary for lung vascular barrier function by establishing the normal balance between RhoA (Ras homolog family member A) and Rac-1-mediated actin cytoskeleton remodeling, a previously unappreciated function for the atypical GEF family of molecules. Our studies also identify S1P as a potential upstream regulator of DOCK4 activity.

Indexed as

Endothelial Cellsrho GTP-Binding ProteinsAdherens JunctionsAnimalsCapillary PermeabilityCells, CulturedEndothelium, VascularGTPase-Activating ProteinsGuanine Nucleotide Exchange FactorsLungMiceDock4 protein, mouseGTPase-Activating ProteinsGuanine Nucleotide Exchange Factorsrho GTP-Binding Proteinsactin cytoskeletonanimalsendothelial cellslungpermeabilitysphingosine-1-phospate receptor modulatorsthrombin

Identifiers

PMID35477279
PMCPMC9233130
OpenAlexW4225098760

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.