Diabetes causes bone marrow endothelial barrier dysfunction by activation of the RhoA-Rho-associated kinase signaling pathway

Giuseppe Mangialardi, Rajesh Katare, Atsuhiko Oikawa, Marco Meloni, Carlotta Reni, Costanza Emanueli, Paolo Madeddu*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

38 Citations (Scopus)

Abstract

Objective-Diabetes mellitus causes bone marrow (BM) microangiopathy. This study aimed to investigate the mechanisms responsible for BM endothelial dysfunction in diabetes mellitus.

Methods and Results-The analysis of differentially expressed transcripts in BM endothelial cells (BMECs) from type1 diabetic and nondiabetic mice showed an effect of diabetes mellitus on signaling pathways controlling cell death, migration, and cytoskeletal rearrangement. Type-1 diabetic-BMECs displayed high reactive oxygen species levels, increased expression and activity of RhoA and its associated protein kinases Rho-associated kinase 1/Rho-associated kinase 2, and reduced Akt phosphorylation/activity. Likewise, diabetes mellitus impaired Akt-related BMEC functions, such as migration, network formation, and angiocrine factor-releasing activity, and increased vascular permeability. Moreover, high glucose disrupted BMEC contacts through Src tyrosine kinase phosphorylation of vascular endothelial cadherin. These alterations were prevented by constitutively active Akt (myristoylated Akt), Rho-associated kinase inhibitor Y-27632, and Src inhibitors. Insulin replacement restored BMEC abundance, as assessed by flow cytometry analysis of the endothelial marker MECA32, and endothelial barrier function in BM of type-1 diabetic mice.

Conclusion-Redox-dependent activation of RhoA/Rho-associated kinase and Src/vascular endothelial cadherin signaling pathways, together with Akt inactivation, contribute to endothelial dysfunction in diabetic BM. Metabolic control is crucial for maintenance of endothelial cell homeostasis and endothelial barrier function in BM of diabetic mice. (Arterioscler Thromb Vasc Biol. 2013;33:555-564.)

Original languageEnglish
Pages (from-to)555-64
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number3
Early online date10 Jan 2013
DOIs
Publication statusPublished - Mar 2013

Keywords

  • Animals
  • Antigens, CD
  • Antigens, Surface
  • Bone Marrow Cells
  • Cadherins
  • Capillary Permeability
  • Cell Movement
  • Cells, Cultured
  • Diabetes Mellitus, Experimental
  • Diabetes Mellitus, Type 1
  • Diabetic Angiopathies
  • Drug Implants
  • Endothelial Cells
  • Flow Cytometry
  • Hypoglycemic Agents
  • Insulin
  • Male
  • Mice
  • Oxidation-Reduction
  • Oxidative Stress
  • Phosphorylation
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • Time Factors
  • Transfection
  • rho GTP-Binding Proteins
  • rho-Associated Kinases
  • rhoA GTP-Binding Protein
  • src-Family Kinases

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