The minor histocompatibility antigen 1 (HMHA1)/ArhGAP45 is a RacGAP and a novel regulator of endothelial integrity

Vascul Pharmacol. 2018 Feb;101:38-47. doi: 10.1016/j.vph.2017.11.007. Epub 2017 Nov 21.

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.

Keywords: ArhGAP45; Endothelium; HMHA1; Permeability; Rac1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Capillary Permeability*
  • Cell Movement
  • Cells, Cultured
  • Electric Impedance
  • Endothelial Cells / metabolism*
  • Endothelial Progenitor Cells / metabolism
  • Fluorescence Resonance Energy Transfer
  • GTPase-Activating Proteins / genetics
  • GTPase-Activating Proteins / metabolism*
  • Gene Expression Regulation
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Mechanotransduction, Cellular
  • Minor Histocompatibility Antigens / genetics
  • Minor Histocompatibility Antigens / metabolism*
  • Neovascularization, Physiologic
  • Protein Binding
  • RNA Interference
  • Stress, Mechanical
  • Time Factors
  • Transfection
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism

Substances

  • ARHGAP45 protein, human
  • GTPase-Activating Proteins
  • Minor Histocompatibility Antigens
  • RAC1 protein, human
  • rac1 GTP-Binding Protein