The role of adherens junctions and VE-cadherin in the control of vascular permeability.
Endothelial cells control the passage of plasma constituents and circulating cells from blood to the underlying tissues. This specialized function is lost or impaired in several pathological conditions - including inflammation, sepsis, ischemia and diabetes - which leads to severe, and sometimes fatal, organ dysfunction. Endothelial permeability is regulated in part by the dynamic opening and closure of cell-cell adherens junctions (AJs). In endothelial cells, AJs are largely composed of vascular endothelial cadherin (VE-cadherin), an endothelium-specific member of the cadherin family of adhesion proteins that binds, via its cytoplasmic domain, to several protein partners, including p120, beta-catenin and plakoglobin. Endogenous pathways that increase vascular permeability affect the function and organization of VE-cadherin and other proteins at AJs in diverse ways. For instance, several factors, including vascular endothelial growth factor (VEGF), induce the tyrosine phosphorylation of VE-cadherin, which accompanies an increase in vascular permeability and leukocyte diapedesis; in addition, the internalization and cleavage of VE-cadherin can cause AJs to be dismantled. From the knowledge of how AJ organization can be modulated, it is possible to formulate several pharmacological strategies to control the barrier function of the endothelium. We discuss the possible use of inhibitors of SRC and other kinases, of agents that increase cAMP levels, and of inhibitors of lytic enzymes as pharmacological tools for decreasing endothelial permeability.
FIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Italy. elisabetta.dejana@ifom-ieo-campus.it
Elisabetta
E
Dejana
Fabrizio
F
Orsenigo
Maria Grazia
MG
Lampugnani
D000205:Actomyosin / Q000378:metabolism; D022005:Adherens Junctions / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D015820:Cadherins / Q000502:physiology*; D002199:Capillary Permeability / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology*; D006801:Humans; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051178:alpha Catenin / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099152:Cadherin 5
D000205:Actomyosin; D015703:Antigens, CD; D015820:Cadherins; D011505:Protein-Tyrosine Kinases; D014443:Tyrosine; D042461:Vascular Endothelial Growth Factor A; D051178:alpha Catenin; D051176:beta Catenin; D000099152:Cadherin 5; C467484:VEGFA protein, human