title: Diabetes causes bone marrow endothelial barrier dysfunction by activation of the RhoA-Rho-associated kinase signaling pathway.
abstract: OBJECTIVE
  Diabetes mellitus causes bone marrow (BM) microangiopathy. This study aimed to investigate the mechanisms responsible for BM endothelial dysfunction in diabetes mellitus.
  
  
  RESULTS
  The analysis of differentially expressed transcripts in BM endothelial cells (BMECs) from type-1 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.
  
  
  CONCLUSIONS
  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.
authors: Experimental Cardiovascular Medicine, Regenerative Medicine Section Bristol Heart Institute, School of Clinical Sciences University of Bristol, Bristol, UK.
authors: Giuseppe
authors: G
authors: Mangialardi
authors: Rajesh
authors: R
authors: Katare
authors: Atsuhiko
authors: A
authors: Oikawa
authors: Marco
authors: M
authors: Meloni
authors: Carlotta
authors: C
authors: Reni
authors: Costanza
authors: C
authors: Emanueli
authors: Paolo
authors: P
authors: Madeddu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D001854:Bone Marrow Cells / Q000187:drug effects / Q000201:enzymology*; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002465:Cell Movement; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D003925:Diabetic Angiopathies / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology* / Q000235:genetics; D004343:Drug Implants; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D005434:Flow Cytometry; D007004:Hypoglycemic Agents / Q000008:administration & dosage; D007328:Insulin / Q000008:administration & dosage; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D020741:rho GTP-Binding Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D000954:Antigens, Surface; D015820:Cadherins; D004343:Drug Implants; D007004:Hypoglycemic Agents; D007328:Insulin; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020741:rho GTP-Binding Proteins; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D019061:src-Family Kinases; D000099152:Cadherin 5; C095910:MECA-32 antigen, mouse; C066737:RHOA protein, human; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; C515854:Rock1 protein, mouse; C515855:Rock2 protein, mouse; C526380:RhoA protein, mouse