Blood cells and endothelial barrier function

Abstract

The barrier properties of endothelial cells are critical for the maintenance of water and protein balance between the intravascular and extravascular compartments. An impairment of endothelial barrier function has been implicated in the genesis and/or progression of a variety of pathological conditions, including pulmonary edema, ischemic stroke, neurodegenerative disorders, angioedema, sepsis and cancer. The altered barrier function in these conditions is often linked to the release of soluble mediators from resident cells (e.g., mast cells, macrophages) and/or recruited blood cells. The interaction of the mediators with receptors expressed on the surface of endothelial cells diminishes barrier function either by altering the expression of adhesive proteins in the inter-endothelial junctions, by altering the organization of the cytoskeleton, or both. Reactive oxygen species (ROS), proteolytic enzymes (e.g., matrix metalloproteinase, elastase), oncostatin M, and VEGF are part of a long list of mediators that have been implicated in endothelial barrier failure. In this review, we address the role of blood borne cells, including, neutrophils, lymphocytes, monocytes, and platelets, in the regulation of endothelial barrier function in health and disease. Attention is also devoted to new targets for therapeutic intervention in disease states with morbidity and mortality related to endothelial barrier dysfunction.

Keywords:

• Endothelial barrier
• erythrocytes
• leukocytes
• platelets
• vascular permeability

Abbreviations:

• AJ, Adherens junctions
• ANG-1, Angiopoietin 1
• AQP, Aquaporins
• BBB, blood brain barrier
• cAMP, 3'-5'-cyclic adenosine monophosphate
• CNS, Central nervous system
• COPD, Chronic obstructive pulmonary disease
• EAE, Experimental autoimmune encephalomyelitis
• EPAC1, Exchange protein activated by cyclic AMP
• ERK1/2, Extracellular signal-regulated kinases 1 and 2
• FA, Focal adhesions
• FAK, focal adhesion tyrosine kinase
• FoxO1, Forkhead box O1
• GAG, Glycosaminoglycans
• GDNF, Glial cell-derived neurotrophic factor
• GJ, Gap junctions
• GPCR, G-protein coupled receptors
• GTPase, Guanosine 5'-triphosphatase
• HMGB-1, High mobility group box 1
• HRAS, Harvey rat sarcoma viral oncogene homolog
• ICAM-1, Intercellular adhesion molecule 1
• IL-1β, Interleukin 1 beta
• IP3, Inositol 1,4,5-triphosphate
• JAM, Junctional adhesion molecules
• MEK, Mitogen-activated protein kinase kinase
• MLC, Myosin light chain
• MLCK, Myosin light-chain kinase
• MMP, Matrix metalloproteinases
• NO, Nitric oxide
• OSM, Oncostatin M
• PAF, Platelet activating factor
• PDE, Phosphodiesterase
• PKA, Protein kinase A
• PNA, Platelet-neutrophil aggregates
• pSrc, Phosphorylated Src
• Rac1, Ras-related C3 botulinum toxin substrate 1
• Rap1, Ras-related protein 1
• RhoA, Ras homolog gene family, member A
• ROS, Reactive oxygen species
• S1P, Sphingosine-1-phosphate
• SCID, Severe combined immunodeficient
• Shp-2, Src homology 2 domain-containing phosphatase 2
• SOCS-3, Suppressors of cytokine signaling 3
• Src, Sarcoma family of protein kinases
• TEER, Transendothelial electrical resistance
• TJ, Tight junctions
• TGF-beta1, Transforming growth factor-beta1
• TNF-, Tumor necrosis factor alpha
• VCAM-1, Vascular cell adhesion molecule 1
• VE, Vascular endothelial
• VEGF, Vascular endothelial growth factor
• VE-PTP, Vascular endothelial receptor protein tyrosine phosphatase
• VVO, Vesiculo-vacuolar organelle
• ZO, Zonula occludens

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Funding

The authors are supported by grants from the National Heart Lung and Blood Institute (HL26441) (DNG) and from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP, 2011/02438–8) and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq, 470895/2011–0) in Brazil (SFR).