Role of VEGF Receptors in Normal and Psoriatic Human Keratinocytes: Evidence from Irradiation with Different UV Sources

Jian-Wei Zhu,Sui-Qing Cai,Min Zheng,Xian-Jie Wu,Zhong-Fa Lu,Dan Luo,Andrzej T Slominski

doi:10.1371/journal.pone.0055463

Abstract

Vascular endothelial growth factor (VEGF) promotes angiogenesis and plays important roles both in physiological and pathological conditions. VEGF receptors (VEGFRs) are high-affinity receptors for VEGF and are originally considered specific to endothelial cells. We previously reported that VEGFRs were also constitutively expressed in normal human keratinocytes and overexpressed in psoriatic epidermis. In addition, UVB can activate VEGFRs in normal keratinocytes, and the activated VEGFR-2 signaling is involved in the pro-survival mechanism. Here, we show that VEGFRs were also upregulated and activated by UVA in normal human keratinocytes via PKC, and interestingly, both the activated VEGFR-1 and VEGFR-2 protected against UVA-induced cell death. As VEGFRs were over-expressed in psoriatic epidermis, we further investigated whether narrowband UVB (NB-UVB) phototherapy or topical halomethasone monohydrate 0.05% cream could affect their expression. Surprisingly, the over-expressed VEGFRs in psoriatic epidermis were significantly attenuated by both treatments. During NB-UVB therapy, VEGFRs declined first in the basal, and then gradually in the upper psoriatic epidermis. VEGFRs were activated in psoriatic epidermis, their activation was enhanced by NB-UVB, but turned undetectable after whole therapy. This process was quite different from that by halomethasone, in which VEGFRs and phospho-VEGFRs decreased in a gradual, homogeneous manner. Our findings further suggest that UV-induced activation of VEGFRs serves as a pro-survival signal for keratinocytes. In addition, VEGFRs may be involved in the pathological process of psoriasis, and UV phototherapy is effective for psoriasis by directly modulating the expression of VEGFRs.

Highlights

It is known that Vascular endothelial growth factor (VEGF) is expressed by epidermal keratinocytes and is upregulated in wound healing, psoriasis, and other states of increased skin angiogenesis as well as by UV irradiation [1,2,3,4,5,6,7,8,9]
As VEGF receptors (VEGFRs) were found to be overexpressed in psoriatic epidermis and might be involved in the pathogenesis of psoriasis [31], and that narrowband UVB (NBUVB) phototherapy or topical halomethasone monohydrate 0.05% cream has been clinically demonstrated to be effective for psoriasis, we examined whether the expression and activation of VEGFRs in the psoriatic epidermis could be affected by these two treatments
The expression of VEGF receptor-1 (VEGFR-1), VEGFR-2 and NRP-1 is increased and the phosphorylation of VEGFR-1 and VEGFR-2 is promoted by UVA irradiation in normal human keratinocytes and epidermis

Summary

Introduction

It is known that VEGF is expressed by epidermal keratinocytes and is upregulated in wound healing, psoriasis, and other states of increased skin angiogenesis as well as by UV irradiation [1,2,3,4,5,6,7,8,9]. The targeted over-expression of VEGF in the epidermis of transgenic mice results in enhanced skin vascularization [11], and development of chronic inflammatory skin lesions after an acute induction of skin inflammation [12]. UV upregulates VEGF production in keratinocyte-derived cell lines both directly through transcription factor activation and indirectly through cytokine release [6,9]. One of the major acute effects of UV exposure is the induction of erythema, cutaneous inflammation, vascular leakage, and edema formation, all of which are characteristics of sunburn. The angiogenic response induced by UVB in VEGF transgenic mice contributed to cutaneous photodamage but not part of a physiologic repair mechanism [13]

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