Epidermal Vascular Endothelial Growth Factor Research Articles

Epidermal Vascular Endothelial Growth Factor Improved Wound Healing of Patients with Diabetic Foot Ulcer

Diabetic foot ulcer (DFU) is a kind of chronic vascular complications in diabetes. Wound healing in DFU is a complex process where reduced proangiogenic growth factor is an important factor. We studied angiogenesis factors which may contribute to the healing of DFU. Twenty five type 2 diabetes patients with acute DFU were treated with hospital standard procedure and closely observed for 1 month. Biopsies from wound edges were subjected to histopathology assessment and immunohistochemical staining of CD34, bFGF and VEGF. All examination was performed two times consecutively. We observed that granulation tissues developed faster at proximal site of the foot. Weak tissue VEGF was expressed before treatment. Interestingly, VEGF expression in epidermis increased significantly after patients received treatment. Increased VEGF is consistent with increased number of CD34 positive endothelial cells. These data suggest that epidermal VEGF is an important angiogenesis factor and may improve healing in acute DFU receiving standard treatment.

Epidermal Vascular Endothelial Growth Factor Production Is Required for Permeability Barrier Homeostasis, Dermal Angiogenesis, and the Development of Epidermal Hyperplasia: Implications for the Pathogenesis of Psoriasis

Primary abnormalities in permeability barrier function appear to underlie atopic dermatitis and epidermal trauma; a concomitant barrier dysfunction could also drive other inflammatory dermatoses, including psoriasis. Central to this outside-inside view of disease pathogenesis is the epidermal generation of cytokines/growth factors, which in turn signal downstream epidermal repair mechanisms. Yet, this cascade, if sustained, signals downstream epidermal hyperplasia and inflammation. We found here that acute barrier disruption rapidly stimulates mRNA and protein expression of epidermal vascular endothelial growth factor-A (VEGF-A) in normal hairless mice, a specific response to permeability barrier requirements because up-regulation is blocked by application of a vapor-impermeable membrane. Moreover, epidermal vegf(-/-) mice display abnormal permeability barrier homeostasis, attributable to decreased VEGF signaling of epidermal lamellar body production; a paucity of dermal capillaries with reduced vascular permeability; and neither angiogenesis nor epidermal hyperplasia in response to repeated tape stripping (a model of psoriasiform hyperplasia). These results support a central role for epidermal VEGF in the maintenance of epidermal permeability barrier homeostasis and a link between epidermal VEGF production and both dermal angiogenesis and the development of epidermal hyperplasia. Because psoriasis is commonly induced by external trauma [isomorphic (Koebner) phenomenon] and is associated with a prominent permeability barrier abnormality, excess VEGF production, prominent angiogenesis, and epidermal hyperplasia, these results could provide a potential outside-inside mechanistic basis for the development of psoriasis.

Epithelial–mesenchymal interactions in keloid pathogenesis modulate vascular endothelial growth factor expression and secretion

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis during the wound healing process. As epithelial-mesenchymal interactions have been shown to regulate a plethora of genes in wound healing, we hypothesized that these interactions might have a role in modulating VEGF expression and angiogenesis. A two chamber co-culture model was used, wherein normal and keloid keratinocytes and fibroblasts were physically separated by membrane inserts while allowing cytokine diffusion. Cell lysates obtained from keratinocytes co-cultured with fibroblasts demonstrated increased expression of VEGF. An enzyme-linked immunosorbent assay (ELISA) showed significant increase in VEGF expression in co-culture conditioned media compared with controls. Additionally, the conditioned medium from keloid keratinocyte and fibroblast co-cultures increased proliferation and formation of complex three-dimensional capillary-like structures in human umbilical vein endothelial cells, emphasising the importance of epithelial-mesenchymal interactions in the angiogenic process. Immunostaining of keloid tissue localized VEGF in the basal layer of the epidermis and also demonstrated higher blood vessel density than normal skin. Keloid tissue extract also demonstrated increased expression of VEGF compared with normal skin. It is likely that epidermal VEGF exerts significant paracrine control over the dynamics and expression profile of underlying dermal fibroblasts. Addition of the inhibitors WP631, mitoxantrone, and Rapamycin to keloid keratinocyte and fibroblast co-cultures, downregulated secreted VEGF expression in a dose-dependent manner, suggesting therapeutic potential for these compounds in the treatment of keloid scars.

Impaired Contact Hypersensitivity Reaction and Reduced Production of Vascular Endothelial Growth Factor in Tumor Necrosis Factor‐α Gene‐Deficient Mice

Tumor necrosis factor (TNF)-alpha is an important proinflammatory cytokine in contact hypersensitivity (CHS) reactions. Previous efforts to assay CHS in TNF-alpha gene-deficient (-/-) mice have demonstrated a significant reduction in ear skin weight at 24 h following challenge by oxazolone, although the mechanisms of this suppression have not been examined. To further characterize the impaired CHS during evolution of the elicitation phase in TNF-alpha -/- mice and to clarify its mechanisms, focusing on the roles of TNF-alpha and vascular endothelial growth factor (VEGF), we used an established method of CHS assay-sensitization and challenge by trinitrochlorobenzene (TNCB)- in TNF-alpha -/- and wild-type mice. We compared the histopathology of the sequential evolution of CHS between the two groups of mice and assessed both the extent of inflammatory cell infiltration and the degree of dilatation in dermal vessels labeled with CD31. We quantified the production of VEGF in the epidermis at specific time points by using a murine VEGF ELISA kit. The CHS reaction was markedly suppressed in TNF-alpha -/- mice at all time points of the elicitation phase. Histologically, in TNF-alpha -/- mice we observed diminished vascular permeability, reduced numbers of infiltrating inflammatory cells, neutrophils at 12 h, mononuclear cells and eosinophils at 24 h, and a decreased area of dilatation of vessels labeled with CD31. The level of epidermal VEGF in wild type mice increased rapidly after challenge and peaked at 24 h, paralleling the peak of ear swelling. In contrast, the peak level of epidermal VEGF in TNF-alpha -/- mice was significantly reduced. These results suggest that TNF-alpha plays an enhancing role in the elicitation phase of the CHS reaction. Diminished degrees of vascular permeability, dilatation of CD31+ vessels, and inflammatory cell infiltration in TNF-alpha -/- mice are likely to be the result of a lack of TNF-alpha and reduced production of epidermal VEGF.

Keloids demonstrate high-level epidermal expression of vascular endothelial growth factor

Background Keloids are a major cause of morbidity, and arise after operation, injury, or cutaneous infection. Clinically, keloids differ from hypertrophic scars in that they grow beyond the original borders of the injury. Keloids occur most commonly for patients of African and Asian descent, and treatment options are multiple, indicating that there is no entirely satisfactory treatment for keloids. Angiogenesis inhibition has been shown to be effective in treatment of malignancy in both animal models and human beings. Objective We sought to determine whether keloids produce the potent angiogenic factor vascular endothelial growth factor (VEGF). Methods We performed in situ hybridization for VEGF on keloid tissue and normal skin. Results Our study demonstrated abundant production of VEGF in keloids and, surprisingly, the major source of VEGF was the overlying epidermis. Conclusions Our results suggest that the overlying epidermis is the major source of keloid angiogenesis. These findings demonstrate that keloids are angiogenic lesions. Topical antiangiogenic therapy, directed at either down-regulating epidermal VEGF or inhibiting keratinocyte-derived VEGF activity on its endothelial receptors, may be useful in the treatment of keloids.