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Review Cutaneous vascular patterns in psoriasis Giuseppe Micali, MD, Francesco Lacarrubba, MD, Maria Letizia Musumeci, MD PhD, Doriana Massimino, MD, and Maria Rita Nasca, MD PhD Dermatology Clinic, University of Catania, Italy Correspondence Giuseppe Micali, MD Clinica Dermatologica Università di Catania Azienda O.U. Policlinico ‘‘Gaspare Rodolico’’ Via Santa Sofia, 78 95123 Catania Italy E-mail: cldermct@nti.it We have given specific contributions to the manuscript and do not have any potential conflicts of interest, including specific financial interests, relevant to the subject of the manuscript. Abstract Microvascular abnormalities are a characteristic feature of psoriasis and play a crucial role in its pathogenesis. Investigational studies have shown that activated keratinocytes in lesional skin undergo an accelerated epidermal cell turnover and are a major source of pro-angiogenic cytokines, like as VEGF, ESAF, PDECGE/TP, TNF-a, TGF-a and PDGF, suggesting that the epidermis is capable of inducing vascular proliferation. On the other hand, microvascular alterations are essential for the development and persistence of the psoriatic lesions as they provide cellular and tissue nutrition to hyperplastic keratinocytes and promote inflammatory cell migration. Also, dilated and slightly tortuous blood vessels within dermal papillae represent one of the earliest detectable histological changes for all stages of lesional development. Videodermatoscopy is a new non invasive imaging techni- que able to identify modifications of microvascular architecture in vivo and such evaluation will be useful for the dermatologist both for diagnostic and prognostic evaluation, as well as for post-therapeutic follow-up. In this review, the role of microvascular abnormalities in the pathogenesis of psoriasis as well as the mechanisms underlying vascular changes and their primary therapeutic implications will be reviewed and discussed. Introduction Psoriasis is a common inflammatory dermatosis with a chronic-relapsing course characterized by erythematous plaques covered by scales. Vascular modifications of cuta- neous microcirculation in lesional skin represent impor- tant features that have been a matter of speculation. In this review, the role of microvascular abnormalities in the pathogenesis of psoriatic lesions and primary therapeutic implications will be reviewed and discussed. Histopathology of microcirculation in psoriasis Histopathological features of psoriasis vary depending on the evolutionary stage of the lesion. Vascular modifica- tions of cutaneous microcirculation represent one of the earliest detectable histological changes and are typical in all stages of lesional development. In the early psoriatic lesions, vascular modifications include increased permeability and dilation of dermal capillaries and mild dermal edema. This is followed by development of typically dilated and slightly tortuous blood vessels and lymphatic capillaries within elongated dermal papillae (Fig. 1).1 Immunohistochemistry reveals a nearly fourfold increased endothelial vascular surface in psoriatic lesional skin compared with normal skin,2,3 and underlies the importance of angiogenesis in the pathogenesis of psoriasis. Pathogenetic role of microcirculation in psoriasis Studies on psoriatic skin blood flow measured by laser Doppler flowmeter have shown that cutaneous blood flow is 9–13 times greater in lesional skin and 2.5–4.5 times greater in perilesional skin compared with normal skin.3 Two possible explanations have been suggested for this phenomenon: one is a vasodilation and elongation of exist- ing vessels, the other is new vessel formation.4 The first hypothesis seems more realistic, as supported by capillaro- scopic studies demonstrating that the density of capillaries in lesional skin is similar to uninvolved skin, although they appear more dilated, tortuous and extended.4–6 Braverman was the first to suggest a mechanism to explain elongation of the capillary loops in psoriasis: endo- thelial cells in the extrapapillary portion of the venous limb undergo division that leads to a venous configuration of the loop with the intrapapillary venous limb longer than the arterial limb (‘‘venulization’’ phenomenon) (Fig. 2).7,8 249 ª 2010 The International Society of Dermatology International Journal of Dermatology 2010, 49, 249–256 On the contrary, resolution of a psoriatic lesion is characterized by resorption of endothelial cells in the venous limb along with a shortening of the intrapapillary venous limb.9 Ultrastructurally, the intrapapillary venous limb is char- acterized by a single or multilayered basement membrane and bridged fenestrations of the endothelial cell layer.10 This phenotype allows an increased transcapillary loss of albumin and other plasma proteins and migration of inflammatory cells into lesional skin, playing an impor- tant pathogenetic role in the development of a psoriatic lesion.9 Endothelial cell gaps range from 0.03 to 1.9 lm in width. Possible hypotheses to explain such gaps include: a histamine-like response to an unidentified agent that implies a low-grade inflammatory reaction constantly present in psoriatic skin, or an inherent weakness of endothelial cell intercellular junctions, and in such a case, their presence might be indicative of genetic markers for latent psoriasis.9 Support for the first hypothesis lies in the resolution of psoriatic lesions when associated with a decrease in volume of the derma papillae and concomi- tant shortening of venous capillary loops that are replaced with arterial capillaries by resorption of the extraendothe- lial cells in the venous limb.9 Several studies have attempted to assess pro-angiogenic activity within psoriatic skin. Wolf and Harrison demon- strated that psoriatic epidermis has a greater angiogenic activity compared with the skin of normal subjects as well as uninvolved and treated psoriatic skin.11 It is now well recognized that keratinocytes in lesional skin are a major source of pro-angiogenic cytokines in psori- asis, including vascular endothelial growth factor (VEGF), endothelial cell stimulating angiogenesis factor (ESAF), platelet-derived endothelial cell growth factor/thymidine phosphorylase (PDECGE/TP), tumor necrosis factor (TNF)-a, transforming growth factor (TGF)-a and platelet derived epidermal growth factor (PDGF) (Fig. 3).2,12,13 Vascular endothelial growth factor is a homodimeric protein produced predominately by keratinocytes, and to a far lesser extent by fibroblasts, that acts as a potent and selective mitogen for endothelial cells. Studies have shown increased VEGF mRNA in lesional psoriatic keratinocytes and a direct relation between severity of disease and VEGF production.13 Experiments on transgenic mouse models have demonstrated that induced overexpression of VEGF by basal keratinocytes resulted in an expanded superficial dermal microvasculature similar to that seen in psoriatic skin.14 VEGF not only promotes angiogenesis but also enhances vascular permeability, as elevated plasma levels of VEGF are found in patients with erythro- dermic psoriasis. It stimulates secretion of interstitial col- lagenase, thereby suggesting a synergistic role with ESAF in the expansion of the microvasculature in psoriatic pla- ques.12 It has been suggested that morbidity in patients with severe disease may be attributable to circulating VEGF.15 Further studies have identified abnormal levels of urinary proteins in a group of patients with generalized (a) (b) Figure 2 The so-called ‘‘venulization’’ phenomenon in psoriasis. (a) Normal capillary; (b) psoriatic capillary (adapted from: Braverman IM: Microcirculation. In: Roenigk HH, Maibach HI (eds). Psoriasis. 3rd Ed. Marcel Dekker Inc, New York 1998: 399–407) Figure 1 Typical histological vascular changes in psoriatic lesion: presence of dilated and tortuous capillaries in the elongated dermal papillae (H–E, ·100) International Journal of Dermatology 2010, 49, 249–256 ª 2010 The International Society of Dermatology Review Cutaneous vascular patterns in psoriasis Micali et al. 250 pustular psoriasis along with elevated plasma concentra- tions of VEGF, suggesting that VEGF, synthesized in lesional tissue, enters the systemic circulation and induces renal microvasculature hyperpermeability with conse- quent proteinuria.6 Following successful therapy, urinary protein and plasma VEGF levels return to normal.5 These observations, if confirmed, may indicate that plasma VEGF assessment in patients with severe psoriasis may be a useful monitoring technique to influence clinical management and outcome. Endothelial cell stimulating angiogenesis factor is a nonenzymatic, nonproteinaceous angiogenic mediator produced in approximately equal amounts by keratino- cytes and fibroblasts, which stimulates proliferation of microvascular endothelial cells and pericytes in vitro. ESAF is significantly elevated in lesional skin and in serum of patients with psoriasis.12 Moreover, ESAF, apart from its direct mitogenic effects on endothelial cells, is also able to activate the three major matrix metallopro- teinases which are involved in angiogenesis in vitro and to dissociate active enzymes from their tissue inhibitors.16 However, further studies are necessary to determine the mechanisms (both stimulatory and inhibitory) by which its secretion, along with that of VEGF, is regulated.12 Platelet-derived endothelial cell growth factor/thymi- dine phosphorylase is a chemotactic agent which is over- expressed in psoriatic skin.2 It induces endothelial chemotaxis as well as angiogenesis in vitro and in vivo, although it does not directly stimulate endothelial cells proliferation. The angiogenic effects of PDECGE/TP seem to be related to its enzymatic activity. It catalyses the reaction of thymidine and phosphate to thymine and 2-deoxy-D-ribose-1-phosphate (2dDr1P), which can then be dephosphorylated to 2-deoxy-D-ribose (2dDr). This last compound has been identified to be crucial in the angiogenic activity of PDECGE/TP and to act as a chemoattractive for endothelial cell in a dose-dependent fashion.17 Tumor necrosis factor-a is a cytokine produced by keratinocytes and endothelial cells that upregulates expression of some pro-angiogenetic factors, such as VEGF, angiopoietin 2, Tie-2 receptor (tyrosine kinase with immunoglobulin-like loop and EGF homology domains) as well as intercellular/vascular cell adhesion molecules involved in trafficking of lymphocytes to inflammatory lesions.18,19 Expression of TNF-a is elevated in psoriatic skin.20 Transforming growth factor-a is a cytokine with angio- genetic properties.21 Some authors demonstrated an over- expression of TGF-a in psoriatic epidermis compared with uninvolved skin. It was found, using RNA hybridiza- tion techniques, that involved epidermis had a fourfold increase in TGF-a mRNA and a sixfold increase in TGF-a protein compared with uninvolved skin.22 These findings underline the importance of TGF-a in the development of psoriatic vascular changes. Platelet derived epidermal growth factor is a molecule secreted by platelets, macrophages, endothelial cells, Immune inflammatory response Endothelial cell proliferation and microvascular expansion Abnormal epidermal proliferation VEGF, ESAF, PDECGF/TP TNF-α, TGF-α, PDGF* Growth factors, cytokines and cellular mediators Activated keratinocyte *VEGF: Vascular endothelial growth factor, ESAF: Endothelial cell stimulating angiogenesis factor, PDECGF/TP: Platelet-derived endothelial cell growth factor/Thymidine phosphorylase; TNF-α: Tumor necrosis factor-α, TGF-α: Transforming growth factor-α; PDGF: Platelet-derived growth factor. Figure 3 Molecular mechanisms underlying cutaneous vascular pattern in psoriasis (adapted from: Pittelkow MR: Keratinocyte abnormalities and signaling pathways. In: Roenigk HH, Maibach HI (eds). Psoriasis. 3rd Ed. Marcel Dekker Inc, New York 1998: 225–246) ª 2010 The International Society of Dermatology International Journal of Dermatology 2010, 49, 249–256 Micali et al. Cutaneous vascular patterns in psoriasis Review 251 fibroblasts, and keratinocytes, which is currently consid- ered to be one of the most potent angiogenesis inducers.23 It is overexpressed in psoriatic skin.2 Angiopoietins are produced by mesenchymal cells and are expressed at sites of blood vessel proliferation and remodeling in psoriatic skin.20 They seem to have com- plementary and co-ordinated roles with vascular develop- ment in association with VEGF. Angiopoietins bind to two at least different Tie receptors: Tie-1 and Tie-2. Although a ligand for Tie-1 has not yet been defined, it is known that both angiopoietin-1 (Ang-1) and angiopoie- tin-2 (Ang-2) bind to Tie-2, with different activities: Ang- 1 leads to vessel maturation and quiescence, Ang-2 acts as a natural antagonist to Ang-1. In addition, Ang-2 blocks the Ang-1/Tie-2 signal and destabilizes mature blood vessels, preparing them for new sprout formation and invasion.24 Ang-2 expression can be upregulated by VEGF, bFGF and hypoxia and can be down-regulated by Ang-1 and TGF-b.25 Matrix metalloproteinases (MMPs)26 are zinc-depen- dent extracellular endopeptidases normally secreted by endothelial cells that, although not constitutively expressed in skin, can be temporarily induced in response to exogenous signals such as cytokines, growth factors or cell–matrix interactions.27 They are overexpressed in pso- riatic skin and include molecules such as MMP-1, MMP- 2, MMP-9, and Membrane type-MMP. MMPs have the capability to degrade components of the extracellular matrix and seem to play an important role in neovascu- larization.16 Endothelial adhesion molecules, known as integrins, play a key role in angiogenesis as they lead to activation and movement of endothelial cells through cell–matrix interaction.16 Integrins are heterodimers containing a noncovalently linked a and b subunits.28 Molecules with an angiogenetic activity include amb3, amb5, b1, a1b1, a2b1, and a5b1;29 in particular, in vivo assays have shown the importance of amb3 integrin in neovascularization. Specifically, this molecule is constitutively expressed at low levels on quiescent blood vessels but is upregulated on the surface of endothelial cells of newly formed capil- laries after exposure to stimuli such as VEGF.30 Expres- sion of integrin amb3 is reported to be elevated in psoriatic skin.31 Interaction between VEGF and amb3 acti- vates a calcium-dependent signaling pathway that pro- motes endothelial cell migration.32 On the contrary, inhibition of amb3 results in endothelial apoptosis and termination of angiogenetic response.30 Upregulation of a large number of vasoactive molecules suggests that psoriatic lesional skin undergoes multifacto- rial stimulatory mechanisms to induce angiogenesis and that angiogenic factors with differing activities may be acting synergistically. Microcirculation structural changes in the development of psoriatic lesions The concept that a vascular defect plays a major role in the pathogenesis of psoriasis has long been debated. Cutane- ous microvasculature modification is essential to mainte- nance of the clinical lesional state in psoriasis providing cellular and tissue nutrition to hyperplastic keratinocytes and promoting inflammatory cell migration.33 Morphological studies in the past have demonstrated dilated and tortuous capillary loops without epidermal hyperplasia in the dermal papillae of psoriatic lesions.34 Dilated capillaries are reported to persist for up to 9 months after skin returned to normal.35 Moreover, convoluted and dilated capillaries have frequently been found in nonlesional skin of psoriatic patients.34 Some authors concluded that initial stimulus in psoriasis was the dilation of cutaneous microcirculation accompanied by exudates of inflammatory cells and serum in the papilla.36 On the contrary, autoradiographic studies have demon- strated that the labeling index of epidermis basal cell lay- ers (number of labeled basal cell nuclei/number of counted basal cell nuclei · 100 = percentage of labeled basal cells in epidermis) is higher than 5% (normal ranges: 2–5%) prior to the appearance of histologically evident epidermal hyperplasia with dilated and tortuous capillary loops.9,37 Therefore, accelerated epidermal cell turnover appears to be a primary defect in the psoriatic process, while the cutaneous microvasculature may play an important role as modulator.9 In vivo evaluation of cutaneous microvascular patterns in psoriasis Capillaroscopy is a noninvasive technique able to identify modifications of microvascular architecture in vivo in many disorders, including psoriasis. Magnifying lenses that are available vary from 10· to 500·. The first reported evaluation of cutaneous microcircula- tion in psoriatic patients was conducted by Gilje.38 Important diagnostic meaning has subsequently been attributed to capillaroscopy and a specific vascular pattern has been identified in psoriatic lesions.31 In lesional skin, low magnifications (10–50·) are usu- ally not able to provide detailed evaluation of capillary loops. However, they provide a global vision of the vas- cular pattern with a punctiform aspect. In general, visual- ization requires magnifications of 100–400· to correctly define specific morphological characteristics of the vascu- lar pattern. At these magnifications, dilated, elongated, and convoluted capillaries with a typical ‘‘glomerular’’ or ‘‘bushy’’ aspect are seen (Figs 4 and 5).4 The caliber of International Journal of Dermatology 2010, 49, 249–256 ª 2010 The International Society of Dermatology Review Cutaneous vascular patterns in psoriasis Micali et al. 252 the vessels is 12–13 lm compared with 5–6 lm diameter of capillaries in healthy skin.39 At the edge of the psoriatic plaque, capillary loops are elongated with a ‘‘hairpin’’ aspect, arranged parallel to the cutaneous surface.4,38,40 High magnifications (500·) are able to assess coursing of erythrocytes into the vascu- lar lumen. A recent study aimed to determine whether videoder- matoscopy (VD), a technique currently used for study of cutaneous pigmented lesions, might be helpful for evaluation of superficial vascular patterns, has been per- formed in a series of patients affected by palmar and/or plantar dermatoses. Thirty-two subjects with clinically nonspecific, active and untreated palmar and/or plantar erythematous scaly lesions, and with no other skin involvement, were enrolled in an open study. In 15 of 32 patients, VD examination showed the presence of pinpoint-like capillaries linearly arranged along furrows of dermatoglyphics at 50·. At 200·, the same capillaries appeared to be dilated and tortuous, with a ‘‘bushy’’ homogenous aspect in all examined fields, suggesting a diagnosis of psoriasis. In the remaining 17 cases, no evi- dence of ‘‘bushy’’ capillaries was present at 50· or 200·. Histopathology in the first group was consistent with the diagnosis of psoriasis, in the second with eczematous dermatitis. The study suggests that analysis of superficial vascular patterns by VD may represent a useful noninvasive diagnostic tool in palmar and/or plan- tar psoriasis.41 Microvascular proliferation and therapeutic implications Traditionally, psoriasis therapies have focused on treating epidermal hyperplasia that results from abnormal prolif- eration and differentiation of basal keratinocytes. Novel therapeutic interventions have focused on angiogenic pathway modulation.42 Evaluation of microcirculation modifications in lesional skin serves to assess the efficacy of new therapies. The first study describing microcirculation modification following treatment for psoriasis with UVB therapy dates back to ultrastructural studies.43 In the following years other studies described, respectively, modification of the capillary plexus following treatment with methotrexate and topical steroids,44 modification of the psoriatic micro- circulation in periungual fold following PUVA therapy,45 and reduction in length and tortuosity of capillary loops after topical tacalcitol treatment.46 Another study47 used laser doppler velocimetry and trans-epidermal water loss to compare topical calcipotriol and clobetasol efficacy. Thus, treatment efficacy and modification of the superfi- cial capillary pattern in psoriasis appears useful in assess- ing drug efficacy. Therapeutic options for psoriasis that have demonstrated anti-angiogenetic properties include agents such as: infliximab, vitamine D3 analogs, retinoids, cyclosporine A (CyA), razoxane, and pulsed dye laser. Infliximab is a TNF-a inhibitor and a cytokine that plays an important role in the angiogenetic and inflamma- tory processes in psoriasis. Recent studies on patients with psoriatic arthritis treated with infliximab have shown a significant reduction of the genetic and protein expression of some proangiogenetic factors, such as VEGF and MMP.48 In addition to normalization of keratinocyte hyperpro- liferation and differentiation, as well as anti-inflammatory and immunomodulatory action, vitamine D3 analogs such Figure 4 Videodermatoscopy of psoriatic lesion: presence of dilated capillaries with typical ‘‘glomerular’’ pattern (200·) Figure 5 Videodermatoscopy of psoriatic lesions at higher magnification (400·) ª 2010 The International Society of Dermatology International Journal of Dermatology 2010, 49, 249–256 Micali et al. Cutaneous vascular patterns in psoriasis Review 253 as calcipotriol and tacalcitol also have an indirect anti-an- giogenetic activity, perhaps related to decreased metabolic demands of less proliferating epidermis49 and to the reduction in the release of IL-8, a well known proangio- genetic factor. Retinoids consist of both natural and synthetic vita- min A. They modulate keratinocyte differentiation and proliferation, and also possess anti-angiogenetic activity via modulation of keratinocyte VEGF production. In addition, retinoids inhibit keratinocyte VEGF expression by interfering with the activator protein 1 transcription factor.50 Cyclosporine A efficacy is attributed to inhibition of transcription factor activity, particularly nuclear factor of activated T cells, activity which down-regulates expres- sion of some cytokines such as interleukin-1 (IL-1) and interleukin-8 (IL-8). It may thus act by modulating the epidermal cytokine network, and thereby suppressing keratinocyte hyperproliferation, dermal inflammation and angiogenesis.51 Moreover, CyA also mediates its effect through the modulation of VEGF.42 Recently, some authors have demonstrated that CyA inhibits angiogenesis through the inhibition of cyclooxygenase (Cox)-2, the transcription of which is activated by VEGF.52 Razoxane, an anti-mitotic drug, has been shown to have an effect on tumor vascular supply. It has biological similarity to Ang-2. Razoxane is associated with an increased risk of acute myeloid leukemia subsequent to prolonged use, which led to its withdrawal as a viable treatment for psoriasis. However, there has been renewed interest in the anti-angiogenetic effects of razoxane on human tumors.53 Treatment with pulsed dye laser has been associated with significant reduction of the density and length of cutaneous microvessels and with clinical improvement.33 Conclusions In this article, the mechanisms underlying vascular changes and their role in the pathogenesis of psoriatic lesions have been reviewed and discussed. This body of knowledge may help in retrieving useful clues for the identification of unequivocal and typical diagnostic features by noninvasive techniques. It may also be essential to address innovative and promising future therapeutic trends. References 1 Murphy M, Kerr P, Grant-Kels JM. The histopathologic spectrum of psoriasis. Clin Dermatol 2007; 25: 524– 528. 2 Creamer D, Allen MH, Sousa A, et al. Localization of endothelial proliferation and microvascular expansion in active plaque psoriasis. 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