Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia

Abstract

Vascular endothelial growth factor-A (VEGF-A) expression is up-regulated in several inflammatory diseases including psoriasis, delayed-type hypersensitivity (DTH) reactions, and rheumatoid arthritis. To directly characterize the biologic function of VEGF-A in inflammation, we evaluated experimental DTH reactions induced in the ear skin of transgenic mice that overexpress VEGF-A specifically in the epidermis. VEGF-A transgenic mice underwent a significantly increased inflammatory response that persisted for more than 1 month, whereas inflammation returned to baseline levels within 7 days in wild-type mice. Inflammatory lesions in VEGF-A transgenic mice closely resembled human psoriasis and were characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of dermal CD4 ؉ T-lymphocytes and epidermal CD8 ؉ lymphocytes. Surprisingly, VEGF-A also promoted lymphatic vessel proliferation and enlargement, which might contribute to the increased inflammatory response, as lymphatic vessel enlargement was also detected in human psoriatic skin lesions. Combined systemic treatment with blocking antibodies against VEGF receptor-1 (VEGFR-1) and VEGFR-2 potently inhibited inflammation and also decreased lymphatic vessel size. Together, these findings reveal a central role of VEGF-A in promoting lymphatic enlargement, vascular hyperpermeability, and leukocyte recruitment, thereby leading to persistent chronic inflammation. They also indicate that inhibition of VEGF-A bioactivity might be a new approach to anti-inflammatory therapy. IntroductionVascular endothelial growth factor-A (VEGF-A) is a homodimeric heparin-binding glycoprotein that occurs in at least 4 isoforms of 121, 165, 189, and 201 amino acids, as a result of alternative splicing (corresponding murine proteins are one amino acid shorter). VEGF-A binds to the 2 type III receptor tyrosine kinases VEGF receptor-1 (VEGFR-1, Flt-1) and VEGFR-2 (KDR or Flk-1), which are primarily expressed by vascular endothelial cells. 1,2 VEGF-A165 also binds to the nonkinase receptors neuropilin 1 and 2. 3 VEGF-A stimulates endothelial cell migration, proliferation, and survival in vitro and promotes microvascular permeability and angiogenesis in vivo. 4,5 Previous studies have revealed that VEGF-A expression by epidermal keratinocytes and endothelial expression of VEGF receptors are up-regulated in several inflammatory conditions including psoriasis, 6 delayed-type hypersensitivity reactions, 7 and bullous diseases. 8 However, the biologic importance of VEGF in the pathogenesis of chronic inflammation has remained unclear.The lymphatic vascular system is composed of a network of thin-walled capillaries that drain protein-rich lymph from the extracellular space and thereby maintain normal tissue pressure. 9 Moreover, lymphatic vessels play an important role in the afferent phase of the immune response. 10 Little is known about the role of the lymphatic vascular system in the control of chronic inflammation, however, due to a lack of reliable markers and t...

Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis

“…Not only is it a potent mitogenic factor but it also stimulates ECs to secrete cytokines essential for cell migration and sprouting of new vessels. It has long been supposed that VEGF-A had no association with lymphangiogenesis, however, in two recent experimental studies, VEGF-A overexpression was found to induce formation of new lymph vessels and dilatation of pre-existing ones (Nagy et al, 2002;Kunstfeld et al, 2004). This action was found to be mediated through stimulation of VEGFR-2, a1b1 and a2b1 integrins on the surface of LECs .…”

Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

“…On the other hand, in cases of chronic inflammation, the extensive lymphatic remodeling that occurs can have detrimental affects on normal immune function [1,105,106]. Hyperplastic lymphatics in chronic diseases such as psoriasis, inflammatory bowel disease, chronically-inflamed skin disease and rheumatoid arthritis have negative implications for disease resolution.…”

“…Hyperplastic lymphatics in chronic diseases such as psoriasis, inflammatory bowel disease, chronically-inflamed skin disease and rheumatoid arthritis have negative implications for disease resolution. For these conditions, treatment with anti-VEGF antibodies can, in some cases, promote disease resolution [106][107][108][109]. Furthermore, while vascular angiogenesis can be reversed in chronic inflammation, lymphangiogenic structures seem to persist [103,110].…”

Developmental and pathological lymphangiogenesis: from models to human disease

“…In addition, other inXammatory diseases seem to be associated with lymphatic activation and dysfunction. For example, lymphatic hyperplasia is observed in UVB-irradiation-induced skin inXammation, in a mouse model of chronic skin inXammation resembling psoriasis, and in human psoriatic skin lesions (Kajiya et al 2006;Kunstfeld et al 2004). In chronic airway inXammation induced by Mycoplasma pulmonis, a massive lymphangiogenesis is induced by VEGF-C/-D-producing inXammatory cells, and its blocking resulted in bronchial lymphedema, thus demonstrating the importance of lymphangiogenesis for compensation of vascular leakage during the inXammation (Baluk et al 2005).…”