Airway Administration of Vascular Endothelial Growth Factor siRNAs Induces Transient Airspace Enlargement in Mice
نویسندگان
چکیده
PURPOSE Reduction in the level of vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of pulmonary emphysema. To this end, pharmacological VEGF receptor blockade, and the Cre-lox system models have been utilized to study the effects of VEGF depletion in the lung. These models generally reproduce air space enlargement resembling clinical emphysema. Here we report a potentially more readily available model of lung targeted VEGF depletion by airway administration of VEGF small inhibitory RNA oligonucleotides (siRNAs) in mice. METHODS Airway administration of VEGF siRNAs were done in C57BL/6 mice. The lungs were removed for histology and protein analysis 2, and 4 days later. Airspace enlargement was evaluated by lung volume measurement, and histological analyses. VEGF levels were analyzed by western blot and immunohistochemistry. RESULTS Airway administration of VEGF siRNAs induced transient air space enlargement in the mouse lung morphologically resembling the previously reported models of pulmonary emphysema. VEGF expression was significantly reduced in the lung, particularly in the alveolar septal cells. We also found that in this particular model, sequential airway administration of recombinant VEGF protein attenuated this air space enlargement. Additionally, we found that airway administration of DCI, a combination of dexamethasone, 3'-5'-cyclic adenosine monophosphate, and isobutylmethylxanthine attenuated the air space enlargement in this particular model, at least in part through the recovery of lung VEGF expression. CONCLUSIONS The pathogenesis of pulmonary emphysema is likely to be multifaceted, but the present mouse model may be useful in dissecting the involvement of VEGF in pulmonary emphysema.
منابع مشابه
Decrease of Serum Vascular Endothelial Growth Factor, along with its Ocular Level, after the Periocular Injection of Celecoxib and Propranolol in Streptozotocin-induced Diabetic Mouse Model
Background: There is a direct correlation between ocular vascular endothelial growth factor (VEGF) level and progression of pathological outcomes in diabetic retinopathy. In our previous study, the periocular administration of propranolol and celecoxib could significantly reduce ocular VEGF levels in a diabetic mouse model. Here, we investigated the changes of serum VEGF after ...
متن کاملMetalloproteinases, Mechanical Factors and Vascular Remodeling
Chronic increases in arterial blood flow elicit an adaptive response of the arterial wall, leading to vessel enlargement and reduction in wall shear stress to physiological baseline value. Release of nitric oxide from endothelial cells exposed to excessive shear is a fundamental step in the remodeling process, and potentially triggers a cascade of events, including growth factor induction and m...
متن کاملDetermination of Vascular Endothelial- and Fibroblast-Growth Factor Receptors in a Mouse Fibrosarcoma Tumor Model Following Photodynamic Therapy
The role of angiogenic molecules, like vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) in tumor angiogenesis was well confirmed. Photodynamic therapy (PDT) action is, to very high degree, based on tumor vasculature damage. Therefore, it seemed to be important to evaluate growth factor receptors after PDT. The extent of receptor expression was studied by immuno-histo...
متن کاملAdenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes.
Vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) are important regulators of blood and lymphatic vessel growth and vascular permeability. The VEGF-C/VEGFR-3 signaling pathway is crucial for lymphangiogenesis, and heterozygous inactivating missense mutations of the VEGFR-3 gene are associated with hereditary lymphedema. However, VEGF-C can have potent effects on blood ves...
متن کامل