Angiogenesis in Chronic Inflammatory Skin Disorders

Abstract

Angiogenesis, the growth of new blood vessels from preexisting vessels, is associated with inflammation in various pathological conditions. Well-known angiogenetic factors include vascular endothelial growth factor (VEGF), angiopoietins, platelet-derived growth factor, transforming growth factor-β, and basic fibroblast growth factor. Yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) have recently been added to an important angiogenic factor. Accumulating evidence indicates associations between angiogenesis and chronic inflammatory skin diseases. Angiogenesis is deeply involved in the pathogenesis of psoriasis. VEGF, angiopoietins, tumor necrosis factor-a, interleukin-8, and interleukin-17 are unregulated in psoriasis and induce angiogenesis. Angiogenesis may be involved in the pathogenesis of atopic dermatitis, and in particular, mast cells are a major source of VEGF expression. Angiogenesis is an essential process in rosacea, which is induced by LL-37 from a signal cascade by microorganisms, VEGF, and MMP-3 from mast cells. In addition, angiogenesis by increased VEGF has been reported in chronic urticaria and hidradenitis suppurativa. The finding that VEGF is expressed in inflammatory skin lesions indicates that inhibition of angiogenesis is a useful strategy for treatment of chronic, inflammatory skin disorders.

Keywords: angiogenesis; atopic dermatitis; chronic urticaria; hidradenitis suppurativa; psoriasis; rosacea.

Figure 1

Angiogenesis in psoriasis: Th17 cells of psoriasis provoke angiogenesis through IL-17 production. In addition to angiogenesis promotion, expression of other angiogenic factors like VEGF and IL-8 is upregulated by IL-17. Keratinocytes, immune cells like mast cells, secrete a variety of pro-angiogenic factors and cytokines that activate and maintain the inflammatory skin condition of psoriasis.

Figure 2

Angiogenesis in AD: Keratinocyte of AD produce VEGF. In addition, mast cells of AD, stimulated by IL-9 and PGE2, provoke angiogenesis through VEGF-A; such expression is also simulated by IL-17 from Th 17 cells. AD, atopic dermatitis; IL, interleukin, PGE2, prostaglandin E2; Th, T helper cell; VEGF, vascular endothelial growth factor.

Figure 3

Angiogenesis in rosacea: The products of microbes are recognized by TLR 2. Subsequently, TLR 2 activates NALP3 inflammasome, which triggers kallikrein 5. Kallikrein 5 cleaves cathelicidin into LL-37, which triggers angiogenesis and inflammation. NALP3 inflammasome also activates mast cells, which produce inflammatory and angiogenetic factors, such as VEGF. TLR2, Toll-like receptor 2; KLK5, kallikrein5; MMP, metalloproteinase; VEGF, vascular endothelial growth factor.

Figure 4

Angiogenesis in chronic urticaria: Eosinophils and mast cells produce VEGF, histamine, and other inflammatory mediators. Especially, mast cells produce VEGF via the PI3K/Akt/p38 MAPK/HIF-1α signaling pathway. VEGF, vascular endothelial growth factor; PIP3, phosphatidyl inositol 3,4,5 tri-phosphate; HIF, hypoxia-inducible factor-1.