Overexpression of vascular endothelial growth factor (VEGF) receptors on keratinocytes in psoriasis: regulated by calcium independent of VEGF

Abstract

Psoriasis is a common chronic inflammatory disease of the skin characterized by epidermal hyperplasia and angiogenesis. Recently, vascular endothelial growth factor receptors (VEGFRs, including VEGFR-1, VEGFR-2 and VEGFR-3) were found to be expressed in normal human epidermis and associated with proliferation and migration of keratinocytes. The purpose of this study is to investigate the expression of VEGFRs on psoriatic keratinocytes and the roles of calcium and VEGF in regulating VEGFR expression. Skin samples from 17 patients with chronic plaque psoriasis and 11 normal controls were included. The expression of VEGFRs in psoriatic keratinocytes at mRNA and protein levels was determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis. Localization of the VEGFRs in skin lesions was determined by immuno-fluorescent method. Since keratinocyte proliferation and differentiation rely on calcium concentrations, and VEGF is overexpressed in psoriatic epidermis, we further investigated the roles of calcium and VEGF in regulating the expression of VEGFRs. Overexpression of VEGFR-1, VEGFR-2 and VEGFR-3 in psoriatic epidermis was demonstrated both at mRNA and protein levels in vitro. VEGFRs were strongly labeled in non-lesional, perilesional and lesional psoriatic keratinocytes in all viable epidermal stratums in vivo. Furthermore, both exogenous VEGF165 and calcium enhanced the expression of VEGFRs. Calcium also enhanced the expression of VEGF in non-lesional psoriatic keratinocytes, while targeted blockade of VEGF activity by bevacizum-ab could not inhibit calcium-induced up-regulation of protein levels of VEGFRs. We conclude from these results that VEGFRs are overexpressed in lesional psoriatic epidermal keratinocytes. Both calcium and VEGF regulate VEGFRs expression in psoriatic epidermis. More importantly, calcium is a potential regulator for VEGFR independent of VEGF.

Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis

“…5 B and C). Similar results for VEGF, VEGFR1, and VEGFR2 also have been observed previously in human psoriatic skin samples (27,28). Even though protein levels of S100A8 and S100A9 in the antibody staining and the Western blots remained similar, the RNA levels for S100A8 and S100A9 were reduced significantly in epidermal samples of anti-VEGFtreated mice (Fig.…”

Inverse Correlation between Caveolin-1 Expression and Clinical Severity in Psoriasis Vulgaris

“…22 The main pathological features of psoriasis are abnormal keratinocyte hyperplasia and angiogenesis in the dermal papilla layer, factors that are closely related to the course and recurrence of the disease. 1 The results of the present study suggest that cav-1 may be involved in abnormal keratinocyte hyperplasia and angiogenesis in psoriasis and indicate its potential as a target protein for the treatment of psoriasis.…”

“…Abnormal keratinocyte hyperplasia and angiogenesis in the dermal papilla layer are the main pathological features of psoriasis and are closely related to the course and recurrence of this disease. 1 Ki-67, a nonhistone nuclear protein, is a reliable marker that can be used to determine the cell proliferation index (PI) and occurs in all phases of the cell cycle except G 0 ; Ki-67 expression in psoriasis has been shown to reflect the degree of abnormal keratinocyte hyperplasia. 2 CD34, a singlechain transmembrane glycoprotein with a molecular weight of 110 kDa, is widely recognized as a highly sensitive and specific marker for vascular endothelial cells; 3 CD34 can be used to calculate microvessel density (MVD) in the dermal papilla, which reflects the level of angiogenesis in psoriasis.…”

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway

“…In particular, NGF increases the levels of vascular endothelial growth factor (VEGF) in normal neural cells and stimulates angiogenesis in animal models of ischemia (Calza et al, 2001;Cantarella et al, 2002). In psoriasis, overexpression of VEGF can accelerate angiogenesis (Man et al, 2008) and constant delivery of VEGF to the psoriatic skin in the transgenic mouse can result in development of psoriasis-like inflammation (Ren et al, 2009). However, there is limited data about the possible role of NGF regulating VEGF expression in the pathogenesis of psoriasis.…”