The Progression of Inflammation Parallels the Dermal Angiogenesis in a Keratin 14 IL‐4‐Transgenic Model of Atopic Dermatitis

Abstract

The role angiogenesis plays in atopic dermatitis is not well understood. The authors previously demonstrated ultrastructurally dermal microvascular angiogenesis in the IL-4-transgenic mouse model of atopic dermatitis. Here, they determine the angiogenic factors involved in dermal microvascular angiogenesis, regulatory function of inflammatory cytokines on the VEGF-A production, and microvascular permeability in this model. Computer-assisted photometric analyses for immunofluorescence-labeled CD31 demonstrated a progressive increase in blood vessel number, diameter, and percent dermal areas occupied by CD31(+) vessels as the disease evolves in transgenic mice from before disease onset through early and late skin lesions. Similar findings were documented for VEGR2(+) vessels. Quantification of skin angiogenic factor mRNAs showed progressive increase of transcripts of VEGF-A, but not VEGF-B, VEGF-C, or VEGF-D. ELISA showed a similar increase of VEGF-A in the serum and skin of transgenic mice. IL-6 and IFN-gamma stimulated VEGF-A mRNA production in the skin and in primary keratinocytes of transgenic mice. Other skin angiogenic factors that increased included Ang-1, Ang-2, GBP-1, and VE-cadherin. Microvascular leakage began in the transgenic mouse skin before disease onset and peaked in the late stage. In conclusion, IL-6 and IFN-gamma may play important roles in upregulation of VEGF-A, along with other pro-angiogenic factors, to induce dermal microvascular angiogenesis.

Possible pathogenic role of T helper type 9 cells and interleukin (IL)-9 in atopic dermatitis

“…VEGF is a major pro-angiogenic factor involved in many inflammatory diseases, which not only promotes angiogenesis but also enhances vascular permeability. In AD, significantly increased expression of biologically active VEGF has been found in the stratum corneum, which indicates that VEGF may participate in AD histological change of capillary dilatation and dermal oedema, as well as associating with the AD clinical manifestation of erythema and inflammatory oedema [28,29]. In this study, increased IL-9 and VEGF mRNA levels were both detected in AD lesions, in agreement with previous studies [29,30]; in addition, a positive association between IL-9 and VEGF mRNA levels was measured.…”

Angiogenesis in the skin of SHARPIN-deficient mice with chronic proliferative dermatitis

“…An increase of VEGFA has been reported in the skin and blood of patients with atopic dermatitis although the role of this angiogenic factor in the pathogenesis of the disease has not been established (Amarbayasgalan et al, 2012; Koczy-Baron et al, 2012; Zhang et al, 2006). There was also increased expression of Vegfa mRNA and a progressive increase of the concentration of VEGFA protein in skin lesions of K14- Il4 transgenic mice, a model for atopic dermatitis (Chen et al, 2008). In contrast to the cpdm dermatitis, the expression of mRNA encoding for VEGFR2, but not VEGFR1, was increased in these mice.…”

“…In atopic dermatitis, dermal blood vessels may be increased and more prominent, along with dilation of lymphatics (Mihm et al, 1976; Prose and Sedlis, 1960). Transgenic mice that overexpress Il4 in keratinocytes, a model of atopic dermatitis, were reported to have a progressive increase of the number of blood vessels in the dermis in parallel with the inflammation (Chen et al, 2008). In addition, there was an increased number and dilation of lymphatics in the skin of these mice (Shi et al, 2012).…”

Angiogenesis in cutaneous disease: Part II

“…[138][139][140][141] The dermal blood vessels in this mouse model show changes consistent with angiogenesis, including elongation, sprouting, and intussusception. 142 Chen et al 143 recently noted a progressive increase in blood vessel number, diameter, and percent dermal area occupied by CD31 1 and VEGFR2 vessels as the disease evolves from start to a chronic state. They also reported an increase of transcripts of VEGF-A, Ang1, Ang2, guanylate-binding protein-1, and the endothelial cell adhesion molecule, vascular/endothelial-cadherin.…”

“…IL-6 and IFNg were thought to stimulate the VEGF-A mRNA production in the skin. 143 In human AD lesions, VEGF121, an isoform of VEGF-A that mainly regulates vascular permeability, was noted to be overexpressed in the stratum corneum. 144 Groneberg et al 145 hypothesized that participation of mast cells could underlie the neovascular processes in AD.…”