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The minor histocompatibility antigen 1 (HMHA1)/ArhGAP45 is a RacGAP and a novel regulator of endothelial integrity
- Source :
- Amado-Azevedo, J, Reinhard, N R, van Bezu, J, van Nieuw Amerongen, G P, van Hinsbergh, V W M & Hordijk, P L 2018, ' The minor histocompatibility antigen 1 (HMHA1)/ArhGAP45 is a RacGAP and a novel regulator of endothelial integrity ', Vascular Pharmacology, vol. 101, pp. 38-47 . https://doi.org/10.1016/j.vph.2017.11.007, Vascular Pharmacology, 101, 38-47. Elsevier Inc.
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- Endothelial cells line the vasculature and act as gatekeepers that control the passage of plasma, macromolecules and cells from the circulation to the interstitial space. Dysfunction of the endothelial barrier can lead to uncontrolled leak or edema. Vascular leakage is a hallmark of a range of diseases and despite its large impact no specialized therapies are available to prevent or reduce it. RhoGTPases are known key regulators of cellular behavior that are directly involved in the regulation of the endothelial barrier. We recently performed a comprehensive analysis of the effect of all RhoGTPases and their regulators on basal endothelial integrity. In addition to novel positive regulators of endothelial barrier function, we also identified novel negative regulators, of which the ArhGAP45 (also known as HMHA1) was the most significant. We now demonstrate that ArhGAP45 acts as a Rac-GAP (GTPase-Activating Protein) in endothelial cells, which explains its negative effect on endothelial barrier function. Silencing ArhGAP45 not only promotes basal endothelial barrier function, but also increases cellular surface area and induces sprout formation in a 3D-fibrin matrix. Our data further shows that loss of ArhGAP45 promotes migration and shear stress adaptation. In conclusion, we identify ArhGAP45 (HMHA1) as a novel regulator, which contributes to the fine-tuning of the regulation of basal endothelial integrity.
- Subjects :
- rac1 GTP-Binding Protein
0301 basic medicine
Time Factors
Endothelium
Physiology
Regulator
Neovascularization, Physiologic
RAC1
Matrix (biology)
Transfection
Mechanotransduction, Cellular
Capillary Permeability
Minor Histocompatibility Antigens
03 medical and health sciences
Interstitial space
Cell Movement
Electric Impedance
Fluorescence Resonance Energy Transfer
Human Umbilical Vein Endothelial Cells
medicine
Minor histocompatibility antigen
Humans
Gene silencing
Cells, Cultured
Endothelial Progenitor Cells
Pharmacology
Chemistry
GTPase-Activating Proteins
Endothelial Cells
Cell biology
030104 developmental biology
medicine.anatomical_structure
Gene Expression Regulation
Molecular Medicine
RNA Interference
Stress, Mechanical
Function (biology)
Protein Binding
Subjects
Details
- ISSN :
- 15371891
- Volume :
- 101
- Database :
- OpenAIRE
- Journal :
- Vascular Pharmacology
- Accession number :
- edsair.doi.dedup.....76822081db90db8fd4a39be93dd962ce