title: Nascent endothelium initiates Th2 polarization of asthma.
abstract: Asthma airway remodeling is linked to Th2 inflammation. Angiogenesis is a consistent feature of airway remodeling, but its contribution to pathophysiology remains unclear. We hypothesized that nascent endothelial cells in newly forming vessels are sufficient to initiate Th2-inflammation. Vascular endothelial (VE)-cadherin is a constitutively expressed endothelial cell adhesion molecule that is exposed in its monomer form on endothelial tip cells prior to adherens junction formation. Abs targeted to VE-cadherin monomers inhibit angiogenesis by blocking this adherens junction formation. In this study, VE-cadherin monomer Ab reduced angiogenesis in the lungs of the allergen-induced murine asthma model. Strikingly, Th2 responses including, IgE production, eosinophil infiltration of the airway, subepithelial fibrosis, mucus metaplasia, and airway-hyperreactivity were also attenuated by VE-cadherin blockade, via mechanisms that blunted endothelial IL-25 and proangiogenic progenitor cell thymic stromal lymphopoietin production. The results identify angiogenic responses in the origins of atopic inflammation.
authors: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors: Kewal
authors: K
authors: Asosingh
authors: Georgiana
authors: G
authors: Cheng
authors: Weiling
authors: W
authors: Xu
authors: Benjamin M
authors: BM
authors: Savasky
authors: Mark A
authors: MA
authors: Aronica
authors: Xiaoxia
authors: X
authors: Li
authors: Serpil C
authors: SC
authors: Erzurum
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects / Q000276:immunology; D000485:Allergens / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015703:Antigens, CD; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D001854:Bone Marrow Cells / Q000276:immunology; D015820:Cadherins / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D004727:Endothelium / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology; D007378:Interleukins / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010641:Phenotype; D050800:STAT6 Transcription Factor / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D000094632:Thymic Stromal Lymphopoietin; D000099152:Cadherin 5
chemical_list: D000485:Allergens; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015820:Cadherins; D016207:Cytokines; D007073:Immunoglobulin E; D007378:Interleukins; D050800:STAT6 Transcription Factor; D000094632:Thymic Stromal Lymphopoietin; D000099152:Cadherin 5; C442281:Mydgf protein, mouse; C000721967:TSLP protein, mouse