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. 2015 Jul 1;88(3):247–252. doi: 10.15386/cjmed-494

VEGF involvement in psoriasis

MIHAELA ELENA MARINA 1, IULIA IOANA ROMAN 2, ANNE-MARIE CONSTANTIN 1,, CARMEN MIHAELA MIHU 1, ALEXANDRU DUMITRU TĂTARU 3
PMCID: PMC4632878  PMID: 26609252

Abstract

Vascular endothelial growth factor (VEGF) is a key growth factor, regulating the neovascularization, during embryogenesis, skeletal growth, reproductive functions and pathological processes. The VEGF receptors (VEGFR) are present in endothelial cells and other cell types, such as vascular smooth muscle cells, hematopoietic stem cells, monocytes, neurons, macrophages, and platelets.

Angiogenesis is initiated by the activation of vascular endothelial cells through several factors. The excess dermal vascularity and VEGF production are markers of psoriasis.

The pathological role of VEGF/VEGFR signaling during the psoriasis onset and evolution makes it a promising target for the treatment of psoriasis. Antibodies and other types of molecules targeting the VEGF pathway are currently evaluated in arresting the evolution of psoriasis.

Keywords: VEGF, VEGFR, psoriasis

VEGF signaling and expression

Vascular endothelial growth factor (VEGF) is a 40–45 kDa dimeric glycoprotein containing a cysteine knot motif [1,2]. The superfamily of VEGF proteins in mammals contains 5 types: VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PLGF) [3,4]. The VEGF-A is the main component of the VEGF family and usually referred to VEGF. The human VEGF gene is located on chromosome 6p21.3 [4].

There are three receptors for VEGF: VEGFR-1, VEGFR-2 [5] and VEGFR-3 [6]; all are tyrosine kinase receptors (RTKs), with high affinity. Neuropilins (NRPs, NRP-1 and NRP-2) are transmembrane receptors with non-tyrosine kinase activity, specific marker for ECs, which present also high-affinity in binding VEGF [6,7].

VEGFR-1 is essential for the recruitment of hematopoietic precursors and migration of monocytes, while VEGFR-2 and VEGFR-3 regulate VEGF-induced angiogenesis and lymphangiogenesis, respectively [2,8]. The NRP-1 and NRP-2 could enhance the activities of VEGFR-2, but also signal independently [3]. VEGFR-1 and VEGFR-2 may link with NRP-1/2, and NRP-2 could bind VEGF-C or co-express with VEGFR-3 [9,10,11].

VEGFR-1 and -2 are activated by VEGF binding and differ considerably in signaling properties [12,13]. There are also non-signaling co-receptors which modulate VEGF RTKs signaling [3]. VEGFR-1 acts during embryogenesis for normal blood vessel development, VEGFR-2 determines the proliferation and the migration of ECs as well as the increased vascular permeability [3,7,14]. Making more complex the situation, there are isoforms of VEGF-A which presents either a pro- or an anti-angiogenic effect [15].

Initially considered to target specifically the ECs, now it is proved that VEGF acts on many stromal cells [16]. Except VEGFR-3 confined to lymphatic endothelial cells, VEGFR-1 and VEGFR-2 are also present on various cell types such as vascular smooth muscle cells [17,18], hematopoietic stem cells [14], monocytes [19], neurons [20], macrophages [21], and platelets [22], but do not have significant levels in endocrine cells [23].

All layers of the epidermis are positive for VEGFRs and NRPs, except for the most superficial stratum corneum [19,24]. The basal keratinocytes and the keratinocytes in the lower stratum spinosum express on their cytoplasmic membrane VEGFR-1 and VEGFR-2 [25]. Also VEGFR-3 and the neuropilins NRP-1 and NRP-2 are expressed in a uniform pattern in all epidermic layers, except the stratum corneum [6]. When pretreated with VEGFR-2 neutralizing antibody [6], keratinocytes in cell culture showed enhanced proliferation and migration due to secondary treatment with different VEGF concentrations. These data support the idea that VEGFR and NRP expression on the keratinocytes membrane surface may regulate the activity and epidermic cell signaling in an autocrine manner [6,19,26].

VEGF and VEGFR-2 were also detected in epidermal appendages: hair follicle, sebaceous glands, and eccrine sweat glands [27]. An elevated VEGF expression on follicular keratinocytes was correlated with angiogenesis during hair growth cycle [28]. Besides, VEGF-induced follicular cell proliferation is mainly mediated by VEGFR-2 expressed on hair follicle outer root sheath cells and dermal papilla cells [29,30].

VEGF involvement in psoriasis

Psoriasis is a chronic inflammatory disease, which affects skin and small joints. It has an autoimmune mechanism, the autoantigen was not even determined. It can affect 2–4% of the population of Caucasian origin [31]. Most of the patients present psoriatic lesions on scalp, elbows and knees [32].

Histopathological markers of skin in psoriasis include: the infiltration of multiple immune cells, keratinocyte hyperplasia, activated mast cells, and accentuated vascularity in the dermis [5,33]. Psoriasis is also commonly associated with a prominent permeability barrier abnormality, and excess VEGF production [32].

One of pathogenetic mechanisms in psoriasis is represented by the VEGF-induced angiogenesis. The psoriatic patients have high serum levels of VEGF and endothelial cell stimulating angiogenesis factor (ESAF) and the psoriatic severity is correlated with the VEGF serum levels [34,35,36]. Other facts that support the VEGF role in psoriasis are the strong correlation between the polymorphisms of a single nucleotide of the VEGF gene and the psoriasis pathogenesis [37,38] and the overexpression of VEGFR-1/2/3 in the epidermis of psoriatic patients [39]. Moreover, VEGFRs were strongly labeled in non-lesional, perilesional, and lesional psoriatic keratinocytes in all epidermal strata in vivo.

The balance between pro- and anti-angiogenic factors regulates the genesis of new blood vessels. The physiologically neovascularization occurs transiently, for example in wound healing or pregnancy. In pathological processes such as tumor growth or chronic inflammation angiogenesis facilitates the disease progress [40,41].

Several factors with pro-angiogenic effect are expressed at high levels in the psoriatic skin: TNF, TGF-α, VEGF, ESAF, hypoxia inducible factor (HIF), interleukin (IL)-8, IL-17 and angiopoietins [34,40,42]. Combined action of these factors stimulate ECs from dermis to form new blood vessels [43]. The interactions between the pro-angiogenic mediators are very complex; for example, TNF has pro- and anti-angiogenic actions, through inducing others pro-angiogenic factors in ECs, such as basic fibroblast growth factor (bFGF), IL-8 and VEGF [44].

There is a vicious circle: the angiogenic factors bFGF and VEGF activate the ECs, which proliferate and migrate, forming a lumen [45,46], but, at the same time, the extracellular matrix (ECM) is degraded and releases these stored stimulating factors for angiogenesis [5], closing the circle.

The overexpression of VEGF in the skin biopsies of psoriasis patients [43] represents an argument for the important role of VEGF in maintaining the normal functioning of epidermis barrier [47] and for a link existing between epidermal VEGF and keratinocytes hyperplasia. Therefore, it may be sustained that VEGF is involved in keratinocyte proliferation [6,47]. It has been shown by Detmar et al. (1994) that VEGF stimulates in vitro the mitotic activity of keratinocytes and upregulates in both ECs and keratinocytes the VEGFR-1 and VEGFR-2 expression [48]. VEGFR-1 and -2 are detectable in skin lesions of psoriatic patients [6]. Thus, because VEGF increases the expression of VEGFR in keratinocytes and the keratinocytes regulate the VEGF expression, we can support the idea that VEGF has an autocrine action on keratinocyte proliferation [49,50].

Only the epidermal barrier disruption alone does not suffice to produce psoriasis. Other dysfunctions in the immune system contribute to establishing the full psoriatic phenotype [49,50]. There is also a perpetuation of the inflammation process in psoriasis [43]: VEGF increases the expression of cell adhesion molecules from capillaries in formation and increase vessel permeability, thereby favoring the leukocytes migration into the psoriatic skin [51]; this process leads to increased oxygen consumption, activation of hypoxia-induced angiogenic transcription factors such as HIF-1, and perpetuation of this angiogenic/inflammatory cycle of psoriasis [43].

VEGF induces several biological effects on ECs: gene expression, survival, proliferation, migration, nitric oxide (NO) and prostacyclin (PGI2) production, increased permeability, tubulogenesis [52,53]. The important integration between signaling cascades occurs at several points [52]. NO and prostanoids link the post-receptor signaling to biological functions, playing therefore paracrine and autocrine roles [52]. The keratinocyte’s VEGF production is upregulated by oxidized phospholipids, which stimulate angiogenesis via autocrine mechanisms involving VEGF, IL-8, and COX-2-generated prostanoids [54]. VEGF alone does not activate endothelium to induce cell adhesion molecules expression; VEGF “sensitizes” ECs to cytokines, increasing selective pro-inflammatory responses [55]. The autocrine/paracrine cycle contributes to psoriatic angiogenesis and epidermal hyperplasia [56]. In genetically modified mice, the overexpression of VEGF can produce a psoriasiform phenotype, with acanthosis, parakeratosis, subepidermal inflammatory infiltrate, tortuous and dilated dermal capillaries, and epidermal microabscesses [56].

There is also an involvement of TNF-α in psoriatic angiogenesis [57]. TNF-α up-regulates the genetic transcription of VEGF [48,58] and increase keratinocyte’s production of pro-inflammatory cytokines, such as IL-8 [59]. Also, it has been proved that TNF-α inhibitors improve endothelial dysfunction [60] and, in the psoriatic plaque, down-regulate levels of many inflammatory cytokines, including angiopoietins and their receptor [61].

Others cells with potential involvement in psoriasis are the mast cells, which can also produce angiogenesis factors (bFGF, VEGF, IL-8) [33,62]. Mast cells are numerous in the dermis (about 7,000/mm3) and nearby small skin vessels. T cell - mast cell interactions determine degranulation of mast cells [63], but also a cytokine production [64], thus the mast cells are regulating the attraction of polymorphonuclear leukocytes into inflammation sites, in response to infiltrating T1 cells, which plays a central role in the pathogenesis of psoriasis [33].

Recentl findings on T-cell populations (Th17 and regulatory T cells), dendritic cells, macrophages, keratinocyte signal transduction, novel cytokines (IL-22, IL-23, IL-20) suggest that psoriasis pathogenesis consists of distinct stages, each with a specific cell as dominant [50].

VEGF as a pharmacological target in psoriasis

The current therapies for psoriasis have two target points: the immune response and the inhibition of neoangiogenesis factors [32]. Patients with history of malignancies might benefit more from a primarily anti-angiogenic approach [65].

Several VEGF inhibitors were clinically tested in several malignancies as a strategy for the prevention of angiogenesis and vascular leakage [3]. Pharmacological blockade of VEGF signaling to inhibit tumor angiogenesis is clinically approved but the survival benefit is limited as patients invariably acquire resistance [16].

Increasing experimental data have shown the effectiveness of anti-VEGF therapy for the treatment of psoriasis; this therapy can reverse a psoriasis-like skin phenotype. The antibody G6-31, which is potently against human and murine VEGF, demonstrated a therapeutic effect in a mouse model which had psoriasis-like skin inflammation [66].

Bevacizumab, a monoclonal antibody against VEGF, used in the treatment of solid cancers (breast, colorectal, renal cell carcinoma) [67,68] is effective also for psoriasis, which validates the consensus that VEGF signaling plays a crucial role during the pathogenesis of psoriasis [69,70]. Akman et al. (2009) described a patient with complete remission of psoriasis under bevacizumab therapy for metastatic colon cancer [70].

Other types of molecules have been developed to target the VEGF pathway including monoclonal antibodies and small molecule inhibitors against VEGFRs. Ramucirumab, a human IgG1 monoclonal antibody (MAb) targeting VEGFR-2, exhibits effectiveness at eliciting tumor responses [71]. Tanibirumab is another fully human IgG1 MAb and demonstrates successful blocking of VEGF in preclinical studies [72].

The inhibitors of VEGFR, used in cancer patients, may also have positive clinical effects in some psoriatic patients, but are recommended to be used in topical forms to limit the toxicities [73]. At present the following are evaluated for psoriatic ameliorating effects: Sunitinib [73], which inhibits VEGFR-2, platelet derived growth factor receptor (PDGFR) and fibroblast growth factor receptor [74,75] and Pazopanib, which inhibits VEGFR-1, -2, -3, and PDGFR [76].

In transgenic mice treated with Aflibercept (VEGF-inhibitor, a soluble chimeric decoy receptor for VEGF), the epidermal structure was restored and blood vessels number was reduced [56].

Retinoids, commonly used as systemic therapy in psoriasis, can stop the VEGF production. The all-trans retinoic acid (RA) produces the inhibition of VEGF keratinocytes’ production in a genotype-dependent manner [38].

Conclusions

VEGF has an important role in initiating the psoriasis phenotype. The pathological role of VEGF/VEGFR signaling during the psoriasis onset and evolution makes it a promising target for the psoriasis treatment.

Angiogenesis is a central process in the evolution of psoriasis, but it is still under evaluation how effective the anti-angiogenic treatments of psoriasis are.

Acknowledgement

This paper was published under the frame of European Social Found, Human Resources Development Operational Programme 2007–2013, project no. POSDRU/159/1.5/138776.

References

  • 1.Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science. 1989;246(4935):1309–1312. doi: 10.1126/science.2479987. [DOI] [PubMed] [Google Scholar]
  • 2.Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21(2):154–165. doi: 10.1016/j.ceb.2008.12.012. [DOI] [PubMed] [Google Scholar]
  • 3.Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–676. doi: 10.1038/nm0603-669. [DOI] [PubMed] [Google Scholar]
  • 4.Holmes K, Roberts OL, Thomas AM, Cross MJ. Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition. Cell Signal. 2007;19(10):2003–2012. doi: 10.1016/j.cellsig.2007.05.013. [DOI] [PubMed] [Google Scholar]
  • 5.Heidenreich R, Röcken M, Ghoreschi K. Angiogenesis drives psoriasis pathogenesis. Int J Exp Pathol. 2009;90(3):232–248. doi: 10.1111/j.1365-2613.2009.00669.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Man XY, Yang XH, Cai SQ, Yao YG, Zheng M. Immunolocalization and expression of vascular endothelial growth factor receptors (VEGFRs) and neuropilins (NRPs) on keratinocytes in human epidermis. Mol Med. 2006;12(7–8):127–136. doi: 10.2119/2006-00024.Man. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 2006;7(5):359–371. doi: 10.1038/nrm1911. [DOI] [PubMed] [Google Scholar]
  • 8.Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473(7347):298–307. doi: 10.1038/nature10144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Fuh G, Garcia KC, de Vos AM. The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor flt-1. J Biol Chem. 2000;275(35):26690–26695. doi: 10.1074/jbc.M003955200. [DOI] [PubMed] [Google Scholar]
  • 10.Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. 2000;60(2):203–212. [PubMed] [Google Scholar]
  • 11.Wey JS, Stoeltzing O, Ellis LM. Vascular endothelial growth factor receptors: expression and function in solid tumors. Clin Adv Hematol Oncol. 2004;2(1):37–45. [PubMed] [Google Scholar]
  • 12.Shibuya M. Role of VEGF-flt receptor system in normal and tumor angiogenesis. Adv Cancer Res. 1995;67:281–316. doi: 10.1016/s0065-230x(08)60716-2. [DOI] [PubMed] [Google Scholar]
  • 13.Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res. 2006;312(5):549–560. doi: 10.1016/j.yexcr.2005.11.012. [DOI] [PubMed] [Google Scholar]
  • 14.Shibuya M. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual regulator for angiogenesis. Angiogenesis. 2006;9(4):225–230. doi: 10.1007/s10456-006-9055-8. discussion 231. [DOI] [PubMed] [Google Scholar]
  • 15.Harper SJ, Bates DO. VEGF-A splicing: the key to anti-angiogenic therapeutics? Nat Rev Cancer. 2008;8(11):880–887. doi: 10.1038/nrc2505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Moens S, Goveia J, Stapor PC, Cantelmo AR, Carmeliet P. The multifaceted activity of VEGF in angiogenesis - Implications for therapy responses. Cytokine Growth Factor Rev. 2014;25(4):473–482. doi: 10.1016/j.cytogfr.2014.07.009. [DOI] [PubMed] [Google Scholar]
  • 17.Cebe-Suarez S, Zehnder-Fjallman A, Ballmer-Hofer K. The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci. 2006;63(5):601–615. doi: 10.1007/s00018-005-5426-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Ng YS, Krilleke D, Shima DT. VEGF function in vascular pathogenesis. Exp Cell Res. 2006;312(5):527–537. doi: 10.1016/j.yexcr.2005.11.008. [DOI] [PubMed] [Google Scholar]
  • 19.Wilgus TA, Matthies AM, Radek KA, Dovi JV, Burns AL, Shankar R, et al. Novel function for vascular endothelial growth factor receptor-1 on epidermal keratinocytes. Am J Pathol. 2005;167(5):1257–1266. doi: 10.1016/S0002-9440(10)61213-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Selheim F, Holmsen H, Vassbotn FS. Identification of functional VEGF receptors on human platelets. FEBS Lett. 2002;512(1–3):107–110. doi: 10.1016/s0014-5793(02)02232-9. [DOI] [PubMed] [Google Scholar]
  • 21.Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovasc Res. 2005;65(3):550–563. doi: 10.1016/j.cardiores.2004.12.002. [DOI] [PubMed] [Google Scholar]
  • 22.Roy H, Bhardwaj S, Ylä-Herttuala S. Biology of vascular endothelial growth factors. FEBS Lett. 2006;580(12):2879–2887. doi: 10.1016/j.febslet.2006.03.087. [DOI] [PubMed] [Google Scholar]
  • 23.La Rosa S, Uccella S, Finzi G, Albarello L, Sessa F, Capella C. Localization of vascular endothelial growth factor and its receptors in digestive endocrine tumors: correlation with microvessel density and clinicopathologic features. Hum Pathol. 2003;34(1):18–27. doi: 10.1053/hupa.2003.56. [DOI] [PubMed] [Google Scholar]
  • 24.Kurschat P, Bielenberg D, Rossignol-Tallandier M, Stahl A, Klagsbrun M. Neuron restrictive silencer factor NRSF/REST is a transcriptional repressor of neuropilin-1 and diminishes the ability of semaphorin 3A to inhibit keratinocyte migration. J Biol Chem. 2006;281(5):2721–2729. doi: 10.1074/jbc.M507860200. [DOI] [PubMed] [Google Scholar]
  • 25.Gu C, Rodriguez ER, Reimert DV, Shu T, Fritzsch B, Richards LJ, et al. Neuropilin-1 conveys semaphoring and VEGF signaling during neural and cardiovascular development. Dev Cell. 2003;5(1):45–57. doi: 10.1016/s1534-5807(03)00169-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Ancelin M, Chollet-Martin S, Herve MA, Legrand C, El Benna J, Perrot-Applanat M. Vascular endothelial growth factor VEGF189 induces human neutrophil chemotaxis in extravascular tissue via an autocrine amplification mechanism. Lab Invest. 2004;84(4):502–512. doi: 10.1038/labinvest.3700053. [DOI] [PubMed] [Google Scholar]
  • 27.Man XY, Yang XH, Cai SQ, Bu ZY, Wu XJ, Lu ZF, et al. Expression and localization of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 in human epidermal appendages: a comparison study by immunofluorescence. Clin Exp Dermatol. 2009;34(3):396–401. doi: 10.1111/j.1365-2230.2008.03104.x. [DOI] [PubMed] [Google Scholar]
  • 28.Yano K, Brown LF, Detmar M. Control of hair growth and follicle size by VEGF-mediated angiogenesis. J Clin Invest. 2001;107(4):409–417. doi: 10.1172/JCI11317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Li W, Lu ZF, Man XY, Li CM, Zhou J, Chen JQ, et al. VEGF upregulates VEGF receptor-2 on human outer root sheath cells and stimulates proliferation through ERK pathway. Mol Biol Rep. 2012;39(9):8687–8694. doi: 10.1007/s11033-012-1725-6. [DOI] [PubMed] [Google Scholar]
  • 30.Li W, Man XY, Li CM, Chen JQ, Zhou J, Cai SQ, et al. VEGF induces proliferation of human hair follicle dermal papilla cells through VEGFR-2-mediated activation of ERK. Exp Cell Res. 2012;318(14):1633–1640. doi: 10.1016/j.yexcr.2012.05.003. [DOI] [PubMed] [Google Scholar]
  • 31.Ghoreschi K, Thomas P, Breit S, Dugas M, Mailhammer R, van Eden W, et al. Interleukin-4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nat Med. 2003;9(1):40–46. doi: 10.1038/nm804. [DOI] [PubMed] [Google Scholar]
  • 32.Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet. 2007;370(9583):263–271. doi: 10.1016/S0140-6736(07)61128-3. [DOI] [PubMed] [Google Scholar]
  • 33.Biedermann T, Kneilling M, Mailhammer R, Maier K, Sander CA, Kollias G, et al. Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J Exp Med. 2000;192(10):1441–1452. doi: 10.1084/jem.192.10.1441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Bhushan M, McLaughlin B, Weiss JB, Griffiths CE. Levels of endothelial cell stimulating angiogenesis factor and vascular endothelial growth factor are elevated in psoriasis. Br J Dermatol. 1999;141(6):1054–1060. doi: 10.1046/j.1365-2133.1999.03205.x. [DOI] [PubMed] [Google Scholar]
  • 35.Nielsen HJ, Christensen IJ, Svendsen MN, Hansen U, Werther K, Brünner N, et al. Elevated plasma levels of vascular endothelial growth factor and plasminogen activator inhibitor-1 decrease during improvement of psoriasis. Inflamm Res. 2002;51(11):563–567. doi: 10.1007/pl00012428. [DOI] [PubMed] [Google Scholar]
  • 36.Nofal A, Al-Makhzangy I, Attwa E, Nassar A, Abdalmoati A. Vascular endothelial growth factor in psoriasis: an indicator of disease severity and control. J Eur Acad Dermatol Venereol. 2009;23(7):803–806. doi: 10.1111/j.1468-3083.2009.03181.x. [DOI] [PubMed] [Google Scholar]
  • 37.Young HS, Summers AM, Bhushan M, Brenchley PE, Griffiths CE. Single-nucleotide polymorphisms of vascular endothelial growth factor in psoriasis of early onset. J Invest Dermatol. 2004;122(1):209–215. doi: 10.1046/j.0022-202X.2003.22107.x. [DOI] [PubMed] [Google Scholar]
  • 38.Young HS, Summers AM, Read IR, Fairhurst DA, Plant DJ, Campalani E, et al. Interaction between genetic control of vascular endothelial growth factor production and retinoid responsiveness in psoriasis. J Invest Dermatol. 2006;126(2):453–459. doi: 10.1038/sj.jid.5700096. [DOI] [PubMed] [Google Scholar]
  • 39.Man XY, Yang XH, Cai SQ, Bu ZY, Zheng M. Overexpression of vascular endothelial growth factor (VEGF) receptors on keratinocytes in psoriasis: regulated by calcium independent of VEGF. J Cell Mol Med. 2008;12(2):649–660. doi: 10.1111/j.1582-4934.2007.00112.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Heidenreich R, Röcken M, Ghoreschi K. Angiogenesis: the new potential target for the therapy of psoriasis? Drug News Perspect. 2008;21(2):97–105. doi: 10.1358/dnp.2008.21.2.1188196. [DOI] [PubMed] [Google Scholar]
  • 41.Wieder T, Braumuller H, Kneilling M, Pichler B, Rocken M. T cell-mediated help against tumors. Cell Cycle. 2008;7(19):2974–2977. doi: 10.4161/cc.7.19.6798. [DOI] [PubMed] [Google Scholar]
  • 42.Creamer D, Sullivan D, Bicknell R, Barker J. Angiogenesis in psoriasis. Angiogenesis. 2002;5(4):231–236. doi: 10.1023/a:1024515517623. [DOI] [PubMed] [Google Scholar]
  • 43.Armstrong AW, Voyles SV, Armstrong EJ, Fuller EN, Rutledge JC. Angiogenesis and oxidative stress: common mechanisms linking psoriasis with atherosclerosis. J Dermatol Sci. 2011;63(1):1–9. doi: 10.1016/j.jdermsci.2011.04.007. [DOI] [PubMed] [Google Scholar]
  • 44.Yoshida S, Ono M, Shono T, Izumi H, Ishibashi T, Suzuki H, et al. Involvement of interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor in tumor necrosis factor alpha-dependent angiogenesis. Mol Cell Biol. 1997;17(7):4015–4023. doi: 10.1128/mcb.17.7.4015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Klagsbrun M, Moses MA. Molecular angiogenesis. Chem Biol. 1999;6(8):R217–R224. doi: 10.1016/S1074-5521(99)80081-7. [DOI] [PubMed] [Google Scholar]
  • 46.Carmeliet P. Angiogenesis in health and disease. Nat Med. 2003;9(6):653–660. doi: 10.1038/nm0603-653. [DOI] [PubMed] [Google Scholar]
  • 47.Elias PM, Arbiser J, Brown BE, Rossiter H, Man MQ, Cerimele F, et al. Epidermal vascular endothelial growth factor production is required for permeability barrier homeostasis, dermal angiogenesis, and the development of epidermal hyperplasia: implications for the pathogenesis of psoriasis. Am J Pathol. 2008;173:689–699. doi: 10.2353/ajpath.2008.080088. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, Jackman RW, et al. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med. 1994;180(3):1141–1146. doi: 10.1084/jem.180.3.1141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Bachelez H. Immunopathogenesis of psoriasis: recent insights on the role of adaptive and innate immunity. J Autoimmun. 2005;25(Suppl):69–73. doi: 10.1016/j.jaut.2005.09.025. [DOI] [PubMed] [Google Scholar]
  • 50.Sabat R, Philipp S, Hoflich C, Kreutzer S, Wallace E, Asadullah K, et al. Immunopathogenesis of psoriasis. Exp Dermatol. 2007;16(10):779–798. doi: 10.1111/j.1600-0625.2007.00629.x. [DOI] [PubMed] [Google Scholar]
  • 51.Detmar M, Brown LF, Schon MP, Elicker BM, Velasco P, Richard L, et al. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J Invest Dermatol. 1998;111(1):1–6. doi: 10.1046/j.1523-1747.1998.00262.x. [DOI] [PubMed] [Google Scholar]
  • 52.Zachary I. VEGF signalling: integration and multi-tasking in endothelial cell biology. Biochem Soc Trans. 2003;31(Pt6):1171–1177. doi: 10.1042/bst0311171. [DOI] [PubMed] [Google Scholar]
  • 53.Neufeld G, Cohen T, Gengrinovitch S, Poltorak Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 1999;13(1):19–22. [PubMed] [Google Scholar]
  • 54.Bochkov VN, Philippova M, Oskolkova O, Kadl A, Furnkranz A, Karabeg E, et al. Oxidized phospholipids stimulate angiogenesis via autocrine mechanisms, implicating a novel role for lipid oxidation in the evolution of atherosclerotic lesions. Circ Res. 2006;99(8):900–908. doi: 10.1161/01.RES.0000245485.04489.ee. [DOI] [PubMed] [Google Scholar]
  • 55.Stannard AK, Khurana R, Evans IM, Sofra V, Holmes DI, Zachary I. Vascular endothelial growth factor synergistically enhances induction of E-selectin by tumor necrosis factor-alpha. Arterioscler Thromb Vasc Biol. 2007;27(3):494–502. doi: 10.1161/01.ATV.0000255309.38699.6c. [DOI] [PubMed] [Google Scholar]
  • 56.Xia YP, Li B, Hylton D, Detmar M, Yancopoulos GD, Rudge JS. Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood. 2003;102(1):161–168. doi: 10.1182/blood-2002-12-3793. [DOI] [PubMed] [Google Scholar]
  • 57.Hurlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, Béchir M, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation. 2002;106(17):2184–2187. doi: 10.1161/01.cir.0000037521.71373.44. [DOI] [PubMed] [Google Scholar]
  • 58.Campanati A, Goteri G, Simonetti O, Ganzetti G, Giuliodori K, Giuliano A, et al. Angiogenesis in psoriatic skin and its modifications after administration of etanercept: videocapillaroscopic, histological and immunohistochemical evaluation. Int J Immunopathol Pharmacol. 2009;22(2):371–377. doi: 10.1177/039463200902200214. [DOI] [PubMed] [Google Scholar]
  • 59.Young CN, Koepke JI, Terlecky LJ, Borkin MS, Boyd Savoy L, Terlecky SR. Reactive oxygen species in tumor necrosis factor-alpha-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease. J Invest Dermatol. 2008;128(11):2606–2614. doi: 10.1038/jid.2008.122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Szekanecz Z, Szanto S, Szabo Z, Vancsa A, Szamosi S, Bodnar N, et al. Biologics – beyond the joints. Autoimmun Rev. 2010;9(12):820–824. doi: 10.1016/j.autrev.2010.07.011. [DOI] [PubMed] [Google Scholar]
  • 61.Markham T, Mullan R, Golden-Mason L, Rogers S, Bresnihan B, Fitzgerald O, Fearon U, et al. Resolution of endothelial activation and down-regulation of Tie2 receptor in psoriatic skin after infliximab therapy. J Am Acad Dermatol. 2006;54(6):1003–1012. doi: 10.1016/j.jaad.2006.01.038. [DOI] [PubMed] [Google Scholar]
  • 62.Sayed BA, Christy A, Quirion MR, Brown MA. The master switch: the role of mast cells in autoimmunity and tolerance. Annu Rev Immunol. 2008;26:705–739. doi: 10.1146/annurev.immunol.26.021607.090320. [DOI] [PubMed] [Google Scholar]
  • 63.Inamura N, Mekori YA, Bhattacharyya SP, Bianchine PJ, Metcalfe DD. Induction and enhancement of Fc(epsilon)RI-dependent mast cell degranulation following coculture with activated T cells: dependency on ICAM-1- and leukocyte function-associated antigen (LFA)-1-mediated heterotypic aggregation. J Immunol. 1998;160(8):4026–4033. [PubMed] [Google Scholar]
  • 64.Krishnaswamy G, Lakshman T, Miller AR, Srikanth S, Hall K, Huang SK, et al. Multifunctional cytokine expression by human mast cells: regulation by T cell membrane contact and glucocorticoids. J Interferon Cytokine Res. 1997;17(3):167–176. doi: 10.1089/jir.1997.17.167. [DOI] [PubMed] [Google Scholar]
  • 65.Weischer M, Röcken M, Berneburg M. Calcineurin inhibitors and rapamycin: cancer protection or promotion? Exp Dermatol. 2007;16(5):385–393. doi: 10.1111/j.1600-0625.2007.00555.x. [DOI] [PubMed] [Google Scholar]
  • 66.Schonthaler HB, Huggenberger R, Wculek SK, Detmar M, Wagner EF. Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis. Proc Natl Acad Sci U S A. 2009;106(50):21264–21269. doi: 10.1073/pnas.0907550106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Catt Research Group. Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897–1908. doi: 10.1056/NEJMoa1102673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Hsu JY, Wakelee HA. Monoclonal antibodies targeting vascular endothelial growth factor: current status and future challenges in cancer therapy. BioDrugs. 2009;23(5):289–304. doi: 10.2165/11317600-000000000-00000. [DOI] [PubMed] [Google Scholar]
  • 69.Akman A, Yilmaz E, Mutlu H, Ozdogan M. Complete remission of psoriasis following bevacizumab therapy for colon cancer. Clin Exp Dermatol. 2009;34(5):e202–e204. doi: 10.1111/j.1365-2230.2008.02991.x. [DOI] [PubMed] [Google Scholar]
  • 70.Canavese M, Altruda F, Ruzicka T, Schauber J. Vascular endothelial growth factor (VEGF) in the pathogenesis of psoriasis–a possible target for novel therapies? J Dermatol Sci. 2010;58(3):171–176. doi: 10.1016/j.jdermsci.2010.03.023. [DOI] [PubMed] [Google Scholar]
  • 71.Spratlin J. Ramucirumab (IMC-1121B): Monoclonal antibody inhibition of vascular endothelial growth factor receptor-2. Curr Oncol Reports. 2011;13(2):97–102. doi: 10.1007/s11912-010-0149-5. [DOI] [PubMed] [Google Scholar]
  • 72.Lee SH. Tanibirumab (TTAC-0001): a fully human monoclonal antibody targets vascular endothelial growth factor receptor 2 (VEGFR-2) Arch Pharm Res. 2011;34(8):1223–1226. doi: 10.1007/s12272-011-0821-9. [DOI] [PubMed] [Google Scholar]
  • 73.Keshtgarpour M, Dudek AZ. SU-011248, a vascular endothelial growth factor receptor-tyrosine kinase inhibitor, controls chronic psoriasis. Transl Res. 2007;149(3):103–106. doi: 10.1016/j.trsl.2007.01.003. [DOI] [PubMed] [Google Scholar]
  • 74.Kerbel R, Folkman J. Clinical translation of angiogenesis inhibitors. Nat Rev Cancer. 2002;2(10):727–739. doi: 10.1038/nrc905. [DOI] [PubMed] [Google Scholar]
  • 75.Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24(1):25–35. doi: 10.1200/JCO.2005.02.2194. [DOI] [PubMed] [Google Scholar]
  • 76.Podar K, Anderson KC. Inhibition of VEGF signaling pathways in multiple myeloma and other malignancies. Cell Cycle. 2007;6(5):538–542. doi: 10.4161/cc.6.5.3922. [DOI] [PubMed] [Google Scholar]

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