Vascular endothelial growth factor (VEGF) induces remodeling and enhances TH2-mediated sensitization and inflammation in the lung

Abstract

Exaggerated levels of VEGF (vascular endothelial growth factor) are present in persons with asthma, but the role(s) of VEGF in normal and asthmatic lungs has not been defined. We generated lung-targeted VEGF(165) transgenic mice and evaluated the role of VEGF in T-helper type 2 cell (T(H)2)-mediated inflammation. In these mice, VEGF induced, through IL-13-dependent and -independent pathways, an asthma-like phenotype with inflammation, parenchymal and vascular remodeling, edema, mucus metaplasia, myocyte hyperplasia and airway hyper-responsiveness. VEGF also enhanced respiratory antigen sensitization and T(H)2 inflammation and increased the number of activated DC2 dendritic cells. In antigen-induced inflammation, VEGF was produced by epithelial cells and preferentially by T(H)2 versus T(H)1 cells. In this setting, it had a critical role in T(H)2 inflammation, cytokine production and physiologic dysregulation. Thus, VEGF is a mediator of vascular and extravascular remodeling and inflammation that enhances antigen sensitization and is crucial in adaptive T(H)2 inflammation. VEGF regulation may be therapeutic in asthma and other T(H)2 disorders.

Pulmonary vascular changes in asthma and COPD

“…Within this timeframe, VEGF 165 was also found to induce TGFβ1 production and activation. After 4 months of VEGF 165 overexpression, prominent collagen deposition and features of vascular remodelling, parenchymal remodelling and physiologic dysregulation were found [92]. Physiologic responses to methacholine were also enhanced demonstrating hyperresponsive airways in the VEGF 165 overexpressed mice.…”

Novel uses for anti‐platelet agents as anti‐inflammatory drugs

“…TGFb increases smooth muscle cell mitogenesis in culture, and it has also been suggested to increase airway obstruction by participating in sub-epithelial fibrosis via its chemotactic properties for fibroblasts and neutrophils (Okona-Mensah et al, 1998). VEGF is necessary for angiogenesis during vascular remodelling of ischaemic tissues and also contributes to increases in airflow resistance in obstructive lung disease (Lee et al, 2004). Angiogenesis is also a feature of airway remodelling in asthmatic individuals.…”

Mapping of angiogenic markers for targeting of vectors to tumor vascular endothelial cells

“…In this experiment, the tumor nodule which was followed for growth, was the same nodule subjected to intratumoral injection. We started injecting the tumor bearing mice with the AdmfVII/hIgG 1 Fc vector when the subcutaneous breast reached 50 mm 3 Mice with a dorsal skin fold chamber in which the N202 tumor spheroid (not carrying the histone 2B-GFP gene) was growing on a mammary fat pad explant were injected either with the mfVII-GFP protein (left hand panel) or first injected with the functional mfVII/hIgG 1 Fc protein and then injected 24 h later with the mfVII-GFP protein (right hand panel). One hour following the administration of the mfVII-GFP protein, the mice were killed.…”

“…[1][2][3][4][5][6][7][8] Endothelial cells of the normal vasculature of normal tissues do not divide and form tight junctions that prevent free diffusion of ions and molecules into the tissue. In contrast, endothelial cells of a tumor vasculature contain 15-30% dividing cells and form a leaky endothelium, allowing free diffusion of ions and small molecules into the tumor.…”