Vascular endothelial growth factor (VEGF), first isolated in 1989, is now considered the key mediator for the process of angiogenesis involved in many developmental, physiological, and pathological conditions. Studies have shown that VEGF family consists of 5 isoforms with similar biological activity but differ in their target receptor activity; the most important of them being the VEGF-A. Studies have also defined the presence of 3 types of VEGF receptors predominantly located on vascular endothelial, stromal, and hematopoietic cells. Recent research has shed light on VEGF as a key mediator of angiogenesis in many pathological conditions such as tumor growth and metastasis. Likewise, there have been intensive efforts to clarify the pathogenic role of VEGF/VEGFRs in skin diseases. VEGF and its receptors are also investigated as pivotal players in many skin diseases such as psoriasis, atopic dermatitis, chronic inflammatory skin diseases, phototoxicity, and dysregulated differentiation/proliferation of dermal and epidermal cells. Therefore, in this review, we will discuss the implication of VEGF as a pathogenic biomarker for skin disorders by discussing the available experimental and clinical evidences for the potential role of VEGF in some dermatologic disorders.
Vascular endothelial growth factor, Angiogenesis, Psoriasis, Lichen planus, Wound healing
Karamysheva AF. Mechanisms of angiogenesis. Biochemistry (Mosc). 2008;73(7):751–62.
Salajegheh A. Introduction to Angiogenesis in Normal Physiology, Disease and Malignancy. In: Angiogenesis in Health, Disease and Malignancy. Springer, Cham. 2016.
Adair TH, Montani JP. Angiogenesis. San Rafael (CA): Morgan & Claypool Life Sciences; 2010. Chapter 1, Overview of Angiogenesis. Available from: https://www.ncbi.nlm.nih.gov/books/NBK53238/
Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56(4):549–80.6. Bae ON,
Noh M, Chun YJ, Jeong TC. Keratinocytic vascular endothelial growth factor as a novel biomarker for pathological skin condition. Biomol Ther (Seoul). 2015;23(1):12–18.
Yan B-X, ZhengY-X, Li W, Chen J, Zhou J, Cai S-Q, Zheng M. Comparative expression of PEDF and VEGF in human epidermal keratinocytes and dermal fibroblasts: from normal skin to psoriasis. Discov Med. 2018;25(136):47–56.
Hänel KH, Cornelissen C, Lüscher B, Baron JM. Cytokines and the skin barrier. Int J Mol Sci. 2013;14:6720–45.
Bernard FX, Morel F, Camus M, Pedretti N, Barrault C, Garnier J, Lecron JC. Keratinocytes under fire of proinflammatory cytokines: Bona fide innate immune cells involved in the physiopathology of chronic atopic dermatitis and psoriasis. J Allergy (Cairo). 2012;718–25.
Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Com. 1989;161(2):851–8.
Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004;25(4):581–611.
Muller YA, Christinger HW, Keyt BA, de Vos AM. The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 Å resolution: multiple copy flexibility and receptor binding. Structure. 1997;5(10):1325–38.
Palmer BF, Clegg DJ. Oxygen sensing and metabolic homeostasis. Mol Cell Endocrinol. 2014;397(1–2):51–57.
Shibuya M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: a crucial target for anti- and pro-angiogenic therapies. Genes Cancer. 2011;2(12):1097–105.
Ferrara N, Kerbel RS. Angiogenesis as a therapeutic target. Nature. 2005;438(7070):967–74.
Scaldaferri F, Vetrano S, Sans M, Arena V, Straface G, Stigliano E, Repici A, Sturm A, Malesci A, Panes J, Yla-Herttuala S, Fiocchi C, Danese S. VEGF-A links angiogenesis and inflammation in inflammatory bowel disease pathogenesis. Gastroenterology.2009;136(2):585-95.e5.
Kant S, Seth G, Anthony K. Vascular endothelial growth factor-A (VEGF-A) in vitreous fluid of patients with proliferative diabetic retinopathy. Ann Ophthalmol (Skokie). 2009;41(3-4):170–3.
Stuttfeld E, Ballmer-Hofer K. Structure and function of VEGF receptors. IUBMB Life. 2009;61(9):915–22.
Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling in control of vascular function. Nat Rev Mol Cell Biol. 2006;7:359–71.
Geretti E, Shimizu A, Klagsbrun M. Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis. Angiogenesis. 2008;11:31–9.
Ruiz de Almodovar RC, Lambrechts D, Mazzone M, Carmeliet P. Role and therapeutic potential of VEGF in the nervous system. Physiol Rev. 2009;89:607–48.
Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol. 2016;17:611–25.
Veikkola T, Karkkainen M, Claesson-Welsh L, Alitalo K. Regulation of angiogenesis via vascular endothelial growth factor receptors. Cancer Res. 2000;60(2):203–12.
Sennino B, Kuhnert F, Tabruyn SP, Tabruyn S, Mancuso MR, Hu-Lowe D, Kuo CJ, McDonald DM. Cellular source and amount of vascular endothelial growth factor and platelet-derived growth factor in tumors determine response to angiogenesis inhibitors. Cancer Res. 2009;69(10):4527–36.
Pagès G, Pouysségur J. Transcriptional regulation of the Alsohaimi A.Pathogenic role of VEGF in skin diseases Vascular Endothelial Growth Factor gene–a concert of activating factors. Cardiovasc Res. 2005;65(3):564–73
Ferrara N, Gerber H, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9: 669–76.27. Li YL, Zhao H, Ren XB. Relationship of VEGF/VEGFR with immune and cancer cells: staggering or forward?. Cancer Biol Med. 2016;13(2):206–214.
Kaur S, Chang T, Singh SP, Lim L. Mannan P, Garfield SH, Pendrak M, -Pantoja D, Rosenberg A. CD47 signaling regulates the immunosuppressive activity of VEGF in T cells. J Immunol. 2014;193:3914–24.
Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and evil. Genes Cancer. 2011;2(12):1117–33.
Ramakrishnan S, Anand V, Roy S. Vascular endothelial growth factor signaling in hypoxia and inflammation. J Neuroimmune Pharmacol. 2014;9(2):142–60.
Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology. 2005;69(3):4–10.32. VEGF/VEGFR inhibitors. https://www.drugs.com/drug-class/vegf-vegfr-inhibitors.html. Accessed at Jun 20, 2019.
Brown LF, Yeo KT, Berse B, Yeo TK, Senger DR, Dvorak HF, van de Water L. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med. 1992;176:1375–9.
Frank S, Hübner G, Breier G, Longaker MT, Greenhalgh DG, Werner S. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem. 1995;270(21):12607–13.
Kim HJ, Kim TY. Regulation of vascular endothelial growth factor expression by insulin-like growth factor-II in human keratinocytes, differential involvement of mitogen-activated protein kinases and feedback inhibition of protein kinase C. Br J Dermatol. 2005;152:418–25.
Johnson KE, Wilgus TA. Vascular endothelial growth factor and angiogenesis in the regulation of cutaneous wound repair. Adv Wound Care (New Rochelle). 2014;3(10):647–61.
Yano K, Brown LF, Detmar M. Control of hair growth and follicle size by VEGF-mediated angiogenesis. J Clin Invest. 2001;107(4):409–17.
Laura S. Angelo and Razelle Kurzrock. Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin Cancer Res. 2007;13(10):2825–30.
Johnson KE, Wilgus TA. Multiple roles for VEGF in non-melanoma skin cancer: angiogenesis and beyond. J Skin Cancer. 2012;2012:id483439.
Marina ME, Roman II, Constantin AM, Mihu CM, Tătaru AD. VEGF involvement in psoriasis. Clujul Med. 2015;88(3):247–52.
Nakai K, Yoneda K, Moriue T, Igarashi J, Kosaka H, Kubota Y. HB-EGF-induced VEGF production and eNOS activation depend on both PI3 kinase and MAP kinase in HaCaT cells. J Dermatol Sci. 2009;55:170–78.
Yu XJ, Ren XH, Xu YH, Chen LM, Zhou CL, Li CY. Vasoactive intestinal peptide induces vascular endothelial growth factor production in human HaCaT keratinocytes via MAPK pathway. Neuropeptides. 2010;44:407–11.
Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol. 1996;16:4604–13.
Finkenzeller G, Sparacio A, Technau A, Marme D, Siemeister G. Sp1 recognition sites in the proximal promoter of the human vascular endothelial growth factor gene are essential for platelet-derived growth factor-induced gene expression. Oncogene. 1997;15:669–76.
Scortegagna M, Cataisson C, Martin RJ, Hicklin DJ, Schreiber RD, Yuspa SH, Arbeit JM. HIF-1alpha regulates epithelial inflammation by cell autonomous NFkappaB activation and paracrine stromal remodeling. Blood. 2008;111:3343–54.
Kim H, Kang JS, Lee WJ. The production IL-21 and VEGF in UVB-irradiated human keratinocyte cell line, HaCaT. Immune Netw. 2010;10(2):75–80.
Weir L, Robertson D, Leigh IM, Vass JK, Panteleyev AA. Hypoxia-mediated control of HIF/ARNT machinery in epidermal keratinocytes. Biochim Biophys Acta. 2011;1813:60–72.
Rendon A, Schäkel K. Psoriasis pathogenesis and treatment. Int J Mol Sci. 2019;20(6):1475.49. Huang YH, Kuo CF, Huang LH, Hsieh MY. Familial aggregation of psoriasis and co-aggregation of autoimmune diseases in affected families. J Clin Med. 2019;8(1):115.
Simonetti O, Lucarini G, Goteri G, Zizzi A, Biagini G, Lo Muzio L, Offidani A. VEGF is likely a key factor in the link between inflammation and angiogenesis in psoriasis: results of an immunohistochemical study. Int J Immunopathol Pharmacol. 2006;19(4):751–60.
Detmar M, Brown LF, Claffey KP, Yeo KT, Kocher O, Jackman RW, Berse B, Dvorak HF. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med. 1994;180(3):1141–6.
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):803–6.
Boehncke WH, Schön MP. Animal models of psoriasis. Clin Dermatol. 2007;25(6):596–605.
Chua RA, Arbiser JL. The role of angiogenesis in the pathogenesis of psoriasis. Autoimmunity. 2009;42(7):574–9.
Loft ND, Skov L, Rasmussen MK, Gniadecki R, Dam TN, Brandslund I. Genetic polymorphisms associated with psoriasis and development of psoriatic arthritis in patients with psoriasis. PLoS ONE. 2018;13(2):e0192010.
Greb J, Goldminz A, Elder J. Psoriasis. Nat Rev Dis Primers. 2016;2:16082.
Castela E, Archier E, Devaux S, Gallini A, Aractingi S, Cribier B, Jullien D, Aubin F, Bachelez H, Joly P, Le Maître M, Misery L, Richard MA, Paul C, Ortonne JP. Topical corticosteroids in plaque psoriasis: a systematic review of efficacy and treatment modalities. J Eur Acad Dermatol Venereol. 2012;26(3):36–46.
Liang H, Fan X, Liang F. Effects of methotrex¬ate on serum expression of MMP-9 and VEGF inpatients with psoriasis vulgaris. Pract Pharm Clin Rem. 2010;23(2):234–7.
Andrys C, Borska L. Angiogenic activity in patients with psoriasis is significantly decreased by Goeckerman’s therapy. Arch Dermatol Res. 2007;298(10):479–83.
Markham T., Mullan R., Golden-Mason L. Resolution of endothelial activation and down-regulation of Tie2 receptor in psoriatic skin after infliximab therapy. J Am Acad Dermatol. 2006;54(7):1003–12.
Diaz BV, Lenoir MC, Ladoux A, Frelin C. Regulation of vascular endothelial growth factor expression in human keratinocytes by retinoids. J Biol Chem. 2000;275(12):642–50.
Li W, Man XY, Chen JQ, Zhou J, Cai SQ, Zheng M. Targeting VEGF/VEGFR in the treatment of psoriasis. Discov Med. 2014;18(98):97–104.
Malecic N & Young HS. Novel investigational vascular endothelial growth factor (VEGF) receptor antagonists for psoriasis. Exp Opin Invest Drugs. 2016;25:4:455–62.
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 USA. 2009;106(50):21264–69.
Lavanya N, Jayanthi P, Rao UK, Ranganathan K. Oral lichen planus: An update on pathogenesis and treatment. J Oral Maxillofac Pathol. 2011;15(2):127–32.
Sun L, Yamasaki K, Shirakata Y. Vascular endothelial growth factor is overexpressed in lichen planus keratinocytes and its expression correlates with increased dermal microvessels in lesional skin. Jap J Dermatol. 2000;110(9):1395–402.
Tao X, Huang Y, Li R, Qing R, Ma L, Rhodus NL, Cheng B. Assessment of local angiogenesis and vascular endothelial growth factor in the patients with atrophic-erosive and reticular oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007; 103(5):661–9.
Scardina GA, Ruggieri A, Messina P, Maresi E. Angiogenesis of oral lichen planus: a possible pathogenetic mechanism. Med Oral Patol Oral Cir Bucal. 2009;14(11):e558–62.
Mardani M, Ghabanchi J, Fattahi MJ, Tadbir AA. Serum level of vascular endothelial growth factor in patients with different clinical subtypes of oral lichen planus. Iran J Med Sci. 2012;37(4):233–7.
Rhodus NL, Cheng B, Myers S, Bowles W, Ho V, Ondrey F. A comparison of the pro-inflammatory, NF-kappaB-dependent cytokines: TNF-alpha, IL-1-alpha, IL-6, and IL-8 in different oral fluids from oral lichen planus patients. Clin Immunol. 2005;114:278–83.
Carvalho JF, Blank M, Shoenfeld Y. Vascular endothelial growth factor (VEGF) in autoimmune diseases. J Clin Immunol. 2007; 27(3):246–56.
Angelo LS, Kurzrock R. Vascular endothelial growth factor and its relationship to inflammatory mediators. Clin Cancer Res. 2007;13(10):2825–30.
Varricchi G, Granata F, Loffredo S, Genovese A, Marone G. Angiogenesis and lymphangiogenesis in inflammatory skin disorders. J Am Acad Dermatol. 2015;73(1):144–53.
Chen L, Marble DJ, Agha R, Peterson JD, Becker RP, Jin T, Li J, Chan LS. The progression of inflammation parallels the dermal angiogenesis in a keratin 14 IL-4-transgenic model of atopic dermatitis. Microcirculation. 2008;15(1):49–64.
Zhang Y, Matsuo H, Morita E. Increased production of vascular endothelial growth factor in the lesions of atopic dermatitis. Arch Dermatol Res. 2006;297:425–9.
Zablotna M, Sobjanek M, Glen J, Niedoszytko M, Wilkowska A, Roszkiewicz J, Nedoszytko B. Association between the -1154 G/A promoter polymorphism of the vascular endothelial growth factor gene and atopic dermatitis. J Eur Acad Dermatol Venereol. 2010;24:91–2.
Bernstein JA, Lang DM, Khan DA, Craig T, Dreyfus D, Hsieh F, Sheikh J, Weldon D, Zuraw B, Bernstein DI, Blessing-Moore J, Cox L, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller DE, Spector SL, Tilles SA, Wallace D. The diagnosis and management of acute and chronic urticaria: 2014 update. J Allergy Clin Immunol. 2014;133(5):1270–7.
Tedeschi A, Asero R, Marzano AV, Lorini M, Fanoni D, Berti E, Cugno M. Plasma levels and skin-eosinophil-expression of vascular endothelial growth factor in patients with chronic urticaria. Allergy. 2009;64(11):1616–22.
Jagodzinska J, Polaniak R, Birkner E, Kasperska-Zajac A. Analysis of circulating vascular endothelial growth factor and its soluble receptors in patients with different forms of chronic urticaria. Biomed Res Int. 2015;2015:id578383.
Kim K, Park H, Lim KM. Phototoxicity: its mechanism and animal alternative test methods [published correction appears in Toxicol Res. 2015;31(3):321]. Toxicol Res. 2015;31(2):97–104.
Blaudschun R, Brenneisen P, Wlaschek M, Meewes C, Scharffetter-Kochanek K. The first peak of the UVB irradiationdependent biphasic induction of vascular endothelial growth factor (VEGF) is due to phosphorylation of the epidermal growth factor receptor and independent of autocrine transforming growth factor alpha. FEBS Lett. 2000;474:195–200.
Brenneisen P, Blaudschun R, Gille J, Schneider L, Hinrichs R, Wlaschek M, Eming S, Scharffetter-Kochanek K. Essential role of an activator protein-2 (AP-2)/specificity protein 1 (Sp1) cluster in the UVB-mediated induction of the human vascular growth factor in HaCaT keratinocytes. Biochem J. 2003;369:341–9.
Yano K, Kadoya K, Kajiya K, Hong YK, Detmar M. Ultraviolet B irradiation of human skin induces an angiogenic switch that is mediated by upregulation of vascular endothelial growth factor and by downregulation of thrombospondin-1. Br J Dermatol. 2005;152:115–21.
Gille J, Reisinger K, Asbe-Vollkopf A, Hardt-Weinelt K, Kaufmann R. Ultraviolet-A-induced transactivation of the vascular endothelial growth factor gene in HaCaT keratinocytes is conveyed by activator protein-2 transcription factor. J Invest Dermatol. 2000;115:30–6.
Hordinsky M, Ericson M. Hair Follicle Vascularization and Innervation (2008). In: Blume-Peytavi U, Tosti A, Trüeb R. (eds) Hair Growth and Disorders. Springer, Berlin, Heidelberg.
Mecklenburg L, Tobin DJ, Müller-Röver S, Handjiski B, Wendt G, Peters EM, Pohl S, Moll I, Paus R. Active hair growth (anagen) is associated with angiogenesis. J Invest Dermatol. 2000;114(5):909–16.
MacLauchlan S, Yu J, Parrish M, Asoulin TA, Schleicher M, Krady MM, Zeng J, Huang PL, Sessa WC, Kyriakides TR. Endothelial nitric oxide synthase controls the expression of the angiogenesis inhibitor thrombospondin 2. Proc Natl Acad Sci USA. 2011;108(46):E1137–45.
Trüeb RM. Molecular mechanisms of androgenetic alopecia. Exp Gerontol. 2002;37(8-9):981–90.
Lachgar, Charveron, Gall, Bonafe. Minoxidil upregulates the expression of vascular endothelial growth factor in human hair dermal papilla cells. Br J Dermatol. 1998;138:407–11.
Yum S, Jeong S, Kim D, Lee S, Kim W, Yoo JW, Kim JA, Kwon OS, Kim DD, Min DS, Jung Y. Minoxidil induction of VEGF is mediated by inhibition of HIF-prolyl hydroxylase. Int J Mol Sci. 2017;19(1):E53.
Nowicka D, Maj J, Jankowska-Konsur A, Hryncewicz-Gwóźdź A. Efficacy of diphenylcyclopropenone in alopecia areata: a comparison of two treatment regimens. Postepy Dermatol Alergol. 2018;35(6):577–81.
Simonetti O, Lucarini G, Bernardini ML, Simoncini C, Biagini G, Offidani A. Expression of vascular endothelial growth factor, apoptosis inhibitors (survivin and p16) and CCL27 in alopecia areata before and after diphencyprone treatment: an immunohistochemical study. Br J Dermatol.2004;150(5):940–8.
Bulock KG, Cardia JP, Pavco PA, Levis WR. Diphencyprone Treatment of alopecia areata: postulated mechanism of action and prospects for therapeutic synergy with RNA interference. J Investig Dermatol Symp Proc. 2015;17(2):16–8.