The cutaneous vascular system in chronic skin inflammation

Abstract

The blood and lymphatic vasculature have an important role in skin homeostasis. Angiogenesis and lymphangiogenesis-the growth of new vessels from existing ones-have received tremendous interest because of their role in promoting cancer spread. However, there is increasing evidence that both vessel types also have a major role in acute and chronic inflammatory disorders. Vessels change their phenotype during inflammation (vascular remodeling). In inflamed skin, vascular remodeling consists of a hyperpermeable, enlarged network of vessels with increased blood flow, and influx of inflammatory cells. During chronic inflammation, the activated endothelium expresses adhesion molecules, cytokines, and other molecules that lead to leukocyte rolling, attachment, and migration into the skin. Recent studies reveal that inhibition of blood vessel activation exerts potent anti-inflammatory properties. Thus, anti-angiogenic drugs might be used to treat inflammatory conditions. In particular, topical application of anti-angiogenic drugs might be ideally suited to circumvent the adverse effects of systemic therapy with angiogenesis inhibitors. Our recent results indicate that stimulation of lymphatic vessel growth and function unexpectedly represents a new approach for treating chronic inflammatory disorders.

Figure 1. Schematic overview of the proposed role of blood and lymphatic vessels in chronic skin inflammation

Cutaneous blood vessels contain a monolayer of endothelial cells (red) with a continous basement membrane (gray). Pericytes (blue) cover the blood vascular endothelial cells (BEC). In contrast, lymphatic endothelial cells (LEC, green) lack mural cells and have only a rudimentary basement membrane. They are linked to the extracellular matrix via fibrillin-containing anchoring filaments (green). The lumen of lymphatic vessels is significantly wider and the wall is thinner than that of blood vessels. BEC express VEGFR-1 and VEGFR-2, whereas LEC express VEGFR-2 and VEGFR-3. VEGF-A – which binds both VEGFR-1 and VEGFR-2 - can directly induce blood and lymphatic vascular remodeling. Chronic stimulation of the blood vasculature by VEGF-A leads to vascular remodeling, increased vascular permeability, increased expression of adhesion molecules and chronic skin inflammation. VEGF-C binds to VEGFR-3 and – after proteolytic processing - might also bind to VEGFR-2 (dashed arrows). In contrast, mouse VEGF-D (mVEGF-D) and VEGF-C156S are specific ligands for VEGFR-3. Stimulation of VEGFR-3 leads to lymphangiogenesis and increases lymphatic flow. An expanded network of lymphatic vessels inhibits chronic skin inflammation. Additional effects of lymphatic vessels – such as binding of chemokines (e.g. to the D6 chemokine receptor) – might contribute to the reduction of chronic inflammation.

Figure 2. Blood and lymphatic vessel expansion in psoriatic skin lesion

The number and size of CD31⁺/LYVE-1⁻ blood vessels (red) is increased in lesional psoriatic skin vs. normal skin of healthy donors. CD31⁺/LYVE-1⁺ lymphatic vessel size (green) is also increased in lesional skin of psoriasis patients. Nuclear staining is shown in blue (Hoechst); bar, 100 µm.