Clinical, Cellular, and Molecular Aspects in the Pathophysiology of Rosacea
2011; Elsevier BV; Volume: 15; Issue: 1 Linguagem: Inglês
10.1038/jidsymp.2011.7
ISSN1529-1774
AutoresMartin Steinhoff, Joerg Buddenkotte, Jérôme Aubert, Mathias Sulk, Pawel Novak, Verena D. Schwab, Christian Meß, Ferda Cevikbas, Michel Rivier, Isabelle Carlavan, Sophie Déret, Carine Rosignoli, Dieter Metze, Thomas A. Luger, Johannes J. Voegel,
Tópico(s)Herpesvirus Infections and Treatments
ResumoRosacea is a chronic inflammatory skin disease of unknown etiology. Although described centuries ago, the pathophysiology of this disease is still poorly understood. Epidemiological studies indicate a genetic component, but a rosacea gene has not been identified yet. Four subtypes and several variants of rosacea have been described. It is still unclear whether these subtypes represent a "developmental march" of different stages or are merely part of a syndrome that develops independently but overlaps clinically. Clinical and histopathological characteristics of rosacea make it a fascinating "human disease model" for learning about the connection between the cutaneous vascular, nervous, and immune systems. Innate immune mechanisms and dysregulation of the neurovascular system are involved in rosacea initiation and perpetuation, although the complex network of primary induction and secondary reaction of neuroimmune communication is still unclear. Later, rosacea may result in fibrotic facial changes, suggesting a strong connection between chronic inflammatory processes and skin fibrosis development. This review highlights recent molecular (gene array) and cellular findings and aims to integrate the different body defense mechanisms into a modern concept of rosacea pathophysiology. Rosacea is a chronic inflammatory skin disease of unknown etiology. Although described centuries ago, the pathophysiology of this disease is still poorly understood. Epidemiological studies indicate a genetic component, but a rosacea gene has not been identified yet. Four subtypes and several variants of rosacea have been described. It is still unclear whether these subtypes represent a "developmental march" of different stages or are merely part of a syndrome that develops independently but overlaps clinically. Clinical and histopathological characteristics of rosacea make it a fascinating "human disease model" for learning about the connection between the cutaneous vascular, nervous, and immune systems. Innate immune mechanisms and dysregulation of the neurovascular system are involved in rosacea initiation and perpetuation, although the complex network of primary induction and secondary reaction of neuroimmune communication is still unclear. Later, rosacea may result in fibrotic facial changes, suggesting a strong connection between chronic inflammatory processes and skin fibrosis development. This review highlights recent molecular (gene array) and cellular findings and aims to integrate the different body defense mechanisms into a modern concept of rosacea pathophysiology. erythematotelangiectatic rosacea phymatous rosacea papulopustular rosacea transient receptor potential (TRP) vanilloid receptor 1 Rosacea is a common, almost exclusively facial inflammatory skin disease characterized by erythema and telangiectasia (erythematotelangiectatic rosacea, ETR, subtype I, RI), papulopustular rosacea (PPR, subtype II, RII), and phymatous rosacea (PhR, subtype III, RIII; Figure 1a). Ocular structures may also be involved (ocular rosacea, subtype IV). Several additional variants have been described (Wilkin et al., 2002Wilkin J. Dahl M. Detmar M. et al.Standard classification of rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea.J Am Acad Dermatol. 2002; 46: 584-587Abstract Full Text Full Text PDF PubMed Scopus (630) Google Scholar, Wilkin et al., 2004Wilkin J. Dahl M. Detmar M. et al.Standard grading system for rosacea: report of the National Rosacea Society Expert Committee on the classification and staging of rosacea.J Am Acad Dermatol. 2004; 50: 907-912Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar), although their subdivision into the entity rosacea is not yet clear. Rosacea prevalence is highest (between 2.7 and 10%) in patients of northern European or Celtic heritage (Webster, 2009Webster G.F. Rosacea.Med Clin North Am. 2009; 93: 1183-1194Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar; Abram et al., 2010bAbram K. Silm H. Oona M. Prevalence of rosacea in an Estonian working population using a standard classification.Acta Derm Venereol. 2010; 90: 269-273Crossref PubMed Scopus (67) Google Scholar; McAleer et al., 2010McAleer M.A. Fitzpatrick P. Powell F.C. Papulopustular rosacea: prevalence and relationship to photodamage.J Am Acad Dermatol. 2010; 63: 33-39Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Humans with fair skin (Fitzpatrick skin phenotypes I–II) are more likely to be affected, whereas Asians and African Americans are less affected, indicating a genetic component (Abram et al., 2010aAbram K. Silm H. Maaroos H.I. et al.Risk factors associated with rosacea.J Eur Acad Dermatol Venereol. 2010; 24: 565-571Crossref PubMed Scopus (106) Google Scholar). This is also supported by the finding that often African Americans are affected when one parent is of northern European origin (Steinhoff M, unpublished observation). Rosacea is more common among female patients, and incidence peaks between the ages of 30 and 50 years. Analyzing the molecular and protein profiles of the different rosacea subtypes has increased our understanding of rosacea pathophysiology and will continue to do so. Gene array (Figure 1b and 2b) and subsequent real-time PCR analysis (not shown) indicate that the clinically defined subtypes of rosacea also differ in their gene profile. All rosacea subtypes show a different gene profile compared with healthy skin. Each subtype can be differentiated by a selective gene profile (Figure 1b). Thus, the pathomechanisms of the different subtypes may vary with respect to the molecular pathways and molecules involved. Our gene array analysis indicates that certain genes overlap, which means that a developmental "march" among the different rosacea subtypes can be assumed in most cases (Figure 1). Despite that, it is still unclear whether patients in whom rosacea becomes clinically apparent not earlier than in the PhR subtype undergo a subclinical form of ETR and PPR. The impact of a dysregulatory vascular system in rosacea patients has long been hypothesized (Flint and Wilkin, 1994Flint I.D. Wilkin J.K. Acquired persistent erythematous patch on the neck. Acquired nevus flammeus.Arch Dermatol. 1994; 130: 509-512Crossref PubMed Scopus (3) Google Scholar; Huggenberger and Detmar, 2011Huggenberger R. Detmar M. The cutaneous vascular system in chronic skin inflammation.J Investig Dermatol Symp Proc. 2011; 15: 24-32Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). Substantial evidence indicates that sun exposure is important in the pathophysiology of rosacea (reviewed by Powell, 2005Powell F.C. Clinical practice. Rosacea.N Engl J Med. 2005; 352: 793-803Crossref PubMed Scopus (214) Google Scholar; Marks, 2007Marks R. The enigma of rosacea.J Dermatol Treat. 2007; 18: 326-328Crossref PubMed Scopus (27) Google Scholar; McAleer et al., 2010McAleer M.A. Fitzpatrick P. Powell F.C. Papulopustular rosacea: prevalence and relationship to photodamage.J Am Acad Dermatol. 2010; 63: 33-39Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar; Webster, 2010Webster G.F. An open-label, community-based, 12-week assessment of the effectiveness and safety of monotherapy with doxycycline 40 mg (30-mg immediate-release and 10-mg delayed-release beads).Cutis. 2010; 86: 7-15PubMed Google Scholar). The impact of UV radiation versus heat during sun exposure is still controversial, although clinical experience suggests that both have an impact because flushing can develop from heat without sun exposure (e.g., hot steam from a coffee pot (Wilkin, 1981Wilkin J.K. Oral thermal-induced flushing in erythematotelangiectatic rosacea.J Invest Dermatol. 1981; 76: 15-18Abstract Full Text PDF PubMed Scopus (93) Google Scholar) and vice versa (sun exposure in a cold environment)). Moreover, temperature changes modulate vascular function (Wilkin, 1981Wilkin J.K. Oral thermal-induced flushing in erythematotelangiectatic rosacea.J Invest Dermatol. 1981; 76: 15-18Abstract Full Text PDF PubMed Scopus (93) Google Scholar, Wilkin, 1983Wilkin J.K. Effect of subdepressor clonidine on flushing reactions in rosacea. Change in malar thermal circulation index during provoked flushing reactions.Arch Dermatol. 1983; 119: 211-214Crossref PubMed Scopus (57) Google Scholar; Crawford et al., 2004Crawford G.H. Pelle M.T. James W.D. Rosacea: I. Etiology, pathogenesis, and subtype classification.J Am Acad Dermatol. 2004; 51: 327-341Abstract Full Text Full Text PDF PubMed Scopus (431) Google Scholar) and affect bacterial protein production (Dahl et al., 2004Dahl M.V. Rosas A.J. Schlievert P.M. Temperature regulates bacterial protein production: possible role in rosacea.J Am Acad Dermatol. 2004; 50: 266-272Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Both UV light and temperature changes can activate sensory nerves (Spiro et al., 1987Spiro J. Parker S. Oliver I. et al.Effect of PUVA on plasma and skin immunoreactive alpha-melanocyte stimulating hormone concentrations.Br J Dermatol. 1987; 117: 703-707Crossref PubMed Scopus (15) Google Scholar; McArthur et al., 1998McArthur J.C. Stocks E.A. Hauer P. et al.Epidermal nerve fiber density: normative reference range and diagnostic efficiency.Arch Neurol. 1998; 55: 1513-1520Crossref PubMed Scopus (439) Google Scholar; Roosterman et al., 2006Roosterman D. Goerge T. Schneider S.W. et al.Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.Physiol Rev. 2006; 86: 1309-1379Crossref PubMed Scopus (397) Google Scholar; Aubdool and Brain, 2011Aubdool A.A. Brain S.D. Neurovascular aspects of skin neurogenic inflammation.J Investig Dermatol Symp Proc. 2011; 15: 33-39Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). Thus, an activated nervous system in the skin correlates well with the early phase of rosacea, although it is still unclear whether neuronal activation precedes or follows the inflammatory infiltrate. The extent to which the autonomic and/or sensory nervous system is involved in the neuronal dysregulation during rosacea has received considerable attention, as modulation of α-adrenergic receptors or β-adrenergic blockers is helpful in some patients (Craige and Cohen, 2005Craige H. Cohen J.B. Symptomatic treatment of idiopathic and rosacea-associated cutaneous flushing with propranolol.J Am Acad Dermatol. 2005; 53: 881-884Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar; Shanler and Ondo, 2007Shanler S.D. Ondo A.L. 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It is noteworthy that by gene array analysis and reverse transcriptase PCR we found that substantial upregulation of proinflammatory genes involved in vasoregulation (e.g., adrenergic receptors, tryptophan metabolites, proteases) and neurogenic inflammation (e.g., transient receptor potential (TRP) vanilloid receptor 1 (TRPV1), pituitary adenylate cyclase-activating polypeptide), along with a marked inflammatory infiltrate (Th1 cells, macrophages, mast cells), can already be observed at a very early stage of rosacea, even before it is clinically visible in terms of papules, nodules, or pustules (Figures 1, 2 and 3). Thus, despite its origin, early rosacea has to be regarded as an inflammatory disease characterized by neuroimmune dysfunction and neurovascular dysregulation.Figure 3Histopathological characteristics of rosacea subtypes (erythematotelangiectatic rosacea (ETR), papulopustular rosacea (PPR), phymatous rosacea (PhR)). All three subtypes were stained for inflammatory and immune markers to determine the inflammatory infiltrate and skin structures involved in inflammation and fibrosis (T cells: CD4, CD8; B cells: CD20, CD79a; Langerhans cells: CD1a; macrophages: CD68; natural killer cells: CD56; neutrophils: CD15, elastase; mesenchymal cells: vimentin (VIM); nerves: PGP9.5, NF200; blood vessels: CD31; lymphatic vessels: podoplanin (Podpl)) in the various subtypes. An increased mast cell infiltrate can also be observed in all subtypes of rosacea (Schwab et al., 2011). (b) Bar=200 μm; (a, g, i, j, l–o), bar=100 μm; (c, d, f, h, k, p), bar=50 μm.View Large Image Figure ViewerDownload (PPT)Figure 4Potential role of neurogenic inflammation in the early phase of rosacea. Genetic predisposition, along with exogenous or endogenous trigger factors, stimulates peripheral nerve endings of the skin. Central transmission of neuronal activation leads to facial discomfort (stinging, burning pain), perceived by the central nervous system. The sensory axon reflex of primary afferents in the dermis and epidermis releases vasoactive neuropeptides such as pituitary adenylate cyclase-activating polypeptide or vasoactive intestinal peptide (VIP) into the microenvironment. Binding of neuromediators to high-affinity neuropeptide receptors on arterioles or venules leads to vasodilatation (flushing, erythema) or plasma extravasation (edema). Activation of T cells, macrophages, and mast cells by neuropeptides results in activation or aggravation of inflammatory responses. It is unknown to what extent neuromediators may also exert anti-inflammatory capacities in human skin diseases. Bi-directional communication between the innate immune and nervous systems may aggravate early rosacea leading to chronic disease. Ca2+, calcium; E, epidermis; F, nerve fibre; Na2+, sodium; TRPV1, transient receptor potential (TRP) vanilloid receptor 1.View Large Image Figure ViewerDownload (PPT) The PPR subtype of rosacea consists of an inflammatory infiltrate leading to papules, pustules, and, sometimes even, cysts. Occasionally, neutrophils or B cells are found in rosacea biopsies. Various microbial agents, including Demodex folliculorum, Helicobacter pylori, Staphylococcus epidermidis, or Chlamydiae, have been implicated in the pathophysiology of rosacea (reviewed by Powell, 2005Powell F.C. Clinical practice. Rosacea.N Engl J Med. 2005; 352: 793-803Crossref PubMed Scopus (214) Google Scholar; Lazaridou et al., 2011Lazaridou E. Giannopoulou C. Fotiadou C. et al.The potential role of microorganisms in the development of rosacea.J Dtsch Dermatol Ges. 2011; 9: 21-25PubMed Google Scholar). The studies on H. pylori are contradictory (Mc Aleer et al., 2009Mc Aleer M.A. Lacey N. Powell F.C. The pathophysiology of rosacea.G Ital Dermatol Venereol. 2009; 144: 663-671PubMed Google Scholar; Gallo et al., 2010Gallo R. Drago F. Paolino S. et al.Rosacea treatments: what's new and what's on the horizon?.Am J Clin Dermatol. 2010; 11: 299-303Crossref PubMed Scopus (22) Google Scholar; Tuzun et al., 2010Tuzun Y. Keskin S. Kote E. The role of Helicobacter pylori infection in skin diseases: facts and controversies.Clin Dermatol. 2010; 28: 478-482Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar; Lazaridou et al., 2011Lazaridou E. Giannopoulou C. Fotiadou C. et al.The potential role of microorganisms in the development of rosacea.J Dtsch Dermatol Ges. 2011; 9: 21-25PubMed Google Scholar). As for D. folliculorum, recent studies support its role as a key factor in at least certain subtypes of rosacea, predominantly subtype II, which is characterized by papules and pustules. Increased numbers of Demodex mites have been found in these patients as compared with healthy skin (Lazaridou et al., 2010Lazaridou E. Apalla Z. Sotiraki S. et al.Clinical and laboratory study of rosacea in northern Greece.J Eur Acad Dermatol Venereol. 2010; 24: 410-414Crossref PubMed Scopus (46) Google Scholar). In addition, these mites may harbor bacteria that may exacerbate rosacea (Lacey et al., 2007Lacey N. Delaney S. Kavanagh K. et al.Mite-related bacterial antigens stimulate inflammatory cells in rosacea.Br J Dermatol. 2007; 157: 474-481Crossref PubMed Scopus (199) Google Scholar; McAleer et al., 2010McAleer M.A. Fitzpatrick P. Powell F.C. Papulopustular rosacea: prevalence and relationship to photodamage.J Am Acad Dermatol. 2010; 63: 33-39Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Thus, it is reasonable to hypothesize that Demodex may activate immune mechanisms in predisposed rosacea patients, in whom Demodex serves as a trigger factor leading to exacerbation of the papular and/or pustular phenotype. However, PPR is also found in patients whose lesions have a normal number of Demodex; other yet unknown cofactors can be hypothesized. Our findings of upregulated genes involved in innate immunity and enhanced immune cells (Figures 1, 2 and 3) indicate the involvement of the adaptive and innate immune system in all subtypes of rosacea, but to different extents. Although genes of the innate immune response are activated in all three subtypes of rosacea, the adaptive immune response seems to be more distinct in PPR and PhR and less in ETR (Figures 1 and 2). This is supported by our IHC characterization of the inflammatory infiltrate within the various subtypes of rosacea, suggesting that inflammatory cells of the innate and adaptive immune system are involved (Figure 3). Our gene array and morphometric data further reveal three important issues: First, neutrophils and B cells are only rarely found in certain patients, indicating that multiple trigger factors lead to the same symptom (papule, pustule). IL-8 mRNA is significantly upregulated in PPR, but the trigger that leads to upregulation of IL-8 and thus to neutrophil formation is currently unknown. Second, gene array and quantitative real-time RT-PCR data demonstrate upregulation of genes involved in innate and adaptive immunity, including cathelicidin, which has been implicated in rosacea pathophysiology by interacting with kallikrein-5 (Yamasaki et al., 2007Yamasaki K. Di Nardo A. Bardan A. et al.Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea.Nat Med. 2007; 13: 975-980Crossref PubMed Scopus (561) Google Scholar; Morizane et al., 2010Morizane S. Yamasaki K. Kabigting F.D. et al.Kallikrein expression and cathelicidin processing are independently controlled in keratinocytes by calcium, vitamin D(3), and retinoic acid.J Invest Dermatol. 2010; 130: 1297-1306Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Third, the inflammatory infiltrate in ETR is predominantly perivascular, not periglandular. Accordingly, our gene array studies and histological data do not support an important role for known microbial agents in the early phases of rosacea. However, further investigations about the impact of the innate immune system on neurovascular and neuroimmune function are warranted to fully understand the neuroimmune and immune defense connection in the pathophysiology of rosacea. Although various studies indicate that a lymphomonocytic infiltrate dominates in rosacea, few examined the whole spectrum of involved inflammatory cells in all subtypes of rosacea by immunohistochemistry, including morphometry. Involvement of T cells (Rufli and Buchner, 1984Rufli T. Buchner S.A. T-cell subsets in acne rosacea lesions and the possible role of Demodex folliculorum.Dermatologica. 1984; 169: 1-5Crossref PubMed Scopus (73) Google Scholar), macrophages (Marks and Harcourt-Webster, 1969Marks R. Harcourt-Webster J.N. Histopathology of rosacea.Arch Dermatol. 1969; 100: 683-691Crossref PubMed Scopus (144) Google Scholar), mast cells (Bamford, 2001Bamford J.T. Rosacea: current thoughts on origin.Semin Cutan Med Surg. 2001; 20: 199-206Crossref PubMed Scopus (63) Google Scholar; Aroni et al., 2008Aroni K. Tsagroni E. Kavantzas N. et al.A study of the pathogenesis of rosacea: how angiogenesis and mast cells may participate in a complex multifactorial process.Arch Dermatol Res. 2008; 300: 125-131Crossref PubMed Scopus (72) Google Scholar), and neutrophils (Ramelet and Perroulaz, 1988Ramelet A.A. Perroulaz G. Rosacea: histopathologic study of 75 cases.Ann Dermatol Venereol. 1988; 115: 801-806PubMed Google Scholar; Akamatsu et al., 1990Akamatsu H. Oguchi M. Nishijima S. et al.The inhibition of free radical generation by human neutrophils through the synergistic effects of metronidazole with palmitoleic acid: a possible mechanism of action of metronidazole in rosacea and acne.Arch Dermatol Res. 1990; 282: 449-454Crossref PubMed Scopus (90) Google Scholar; Millikan, 2003Millikan L. The proposed inflammatory pathophysiology of rosacea: implications for treatment.Skinmed. 2003; 2: 43-47Crossref PubMed Scopus (47) Google Scholar) has been described. Plasma cells have been described in PhR (Aloi et al., 2000Aloi F. Tomasini C. Soro E. et al.The clinicopathologic spectrum of rhinophyma.J Am Acad Dermatol. 2000; 42: 468-472Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar). Our IHC and morphometric analyses of rosacea subtypes I–III suggest that the dominating activated cells in rosacea are CD4+ Th1 cells, macrophages, and mast cells (Figure 3; Steinhoff et al., 2010Steinhoff M. Sulk M. Schwab V. et al.Molecular and morphometric characterization of neuroinflammatory and neurovascular changes in the development of rosacea.J Invest Dermatol. 2010; 130 (abstract 088): S15Google Scholar; Schwab et al., 2011Schwab V.D. Sulk M. Seeliger S. et al.Neurovascular and neuroimmune aspects in the pathophysiology of rosacea.J Investig Dermatol Symp Proc. 2011; 15: 53-62Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). It is noteworthy that the early stage of rosacea already presents as a Th1-cell-mediated inflammatory skin disease accompanied by macrophages and mast cells, without enhancement of Langerhans cells, eosinophils, or natural killer cells (Figure 3). Additional trigger factors not yet known seem to activate neutrophils and B cells in rosacea patients under certain conditions, resulting in pustules (neutrophils) and probably development into a hyperglandular–phymatous stage (increased density of B cells). In contrast with other inflammatory skin diseases such as psoriasis, lupus erythematosus, or atopic dermatitis, the crucial cytokines and chemokines that orchestrate the initiation and perpetuation of rosacea are not fully known. Our molecular characterization of the different subtypes of rosacea as compared with healthy human skin by gene array analysis and real-time PCR indicates that a variety of cytokines, chemokines, metalloproteinases, proteases, and reactive oxygen species molecules, as well as lipid mediators, contribute to dysregulation of the inflammatory responses in rosacea (Figure 2a; Gerber et al., 2011Gerber P.A. Buhren B.A. Steinhoff M. et al.Rosacea: the cytokine and chemokine network.J Investig Dermatol Symp Proc. 2011; 15: 40-47Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). Still lacking, however, is a systematic profile of the inflammatory mediators involved in rosacea pathophysiology, both at the gene and protein level. The importance of the vascular cutaneous system in rosacea is supported by the clinical and histopathological characteristics of flushing, erythema, and telangiectasia. Furthermore, edema results from plasma extravasation; i.e., the vascular leakage of blood vessels and rosacea is characterized by edema derived from blood and lymphatic vessels. Edema intensity varies in rosacea, and the maximal clinical stage is represented by morbus morbihan, in which lymphedema is the predominant clinical appearance. Blood and lymphatic vessels have an extraordinary role in skin development, body homeostasis, and wound repair (reviewed by Roosterman et al., 2006Roosterman D. Goerge T. Schneider S.W. et al.Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.Physiol Rev. 2006; 86: 1309-1379Crossref PubMed Scopus (397) Google Scholar; Huggenberger and Detmar, 2011Huggenberger R. Detmar M. The cutaneous vascular system in chronic skin inflammation.J Investig Dermatol Symp Proc. 2011; 15: 24-32Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar; Meyer-Hoffert and Schröder, 2011Meyer-Hoffert U. Schröder J-M Epidermal proteases in the pathogenesis of rosacea.J Investig Dermatol Symp Proc. 2011; 15: 16-23Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). Both are apparently involved in chronic inflammatory diseases such as psoriasis. Recent data indicate that blood and lymphatic vessels are also involved in rosacea (Gomaa et al., 2007Gomaa A.H. Yaar M. Eyada M.M. et al.Lymphangiogenesis and angiogenesis in non-phymatous rosacea.J Cutan Pathol. 2007; 34: 748-753Crossref PubMed Scopus (78) Google Scholar; Smith et al., 2007Smith J.R. Lanier V.B. Braziel R.M. et al.Expression of vascular endothelial growth factor and its receptors in rosacea.Br J Ophthalmol. 2007; 91: 226-229Crossref PubMed Scopus (70) Google Scholar; Aroni et al., 2008Aroni K. Tsagroni E. Kavantzas N. et al.A study of the pathogenesis of rosacea: how angiogenesis and mast cells may participate in a complex multifactorial process.Arch Dermatol Res. 2008; 300: 125-131Crossref PubMed Scopus (72) Google Scholar; Bender et al., 2008Bender A. Zapolanski T. Watkins S. et al.Tetracycline suppresses ATP gamma S-induced CXCL8 and CXCL1 production by the human dermal microvascular endothelial cell-1 (HMEC-1) cell line and primary human dermal microvascular endothelial cells.Exp Dermatol. 2008; 17: 752-760Crossref PubMed Scopus (27) Google Scholar). The crucial growth factors, vasoregulatory molecules, and receptors contributing to the development of vasodilatation, edema formation, or lymphedema are poorly understood in the context of rosacea (Nakamura and Rockson, 2008Nakamura K. Rockson S.G. Molecular targets for therapeutic lymphangiogenesis in lymphatic dysfunction and disease.Lymphat Res Biol. 2008; 6: 181-189Crossref PubMed Scopus (29) Google Scholar; Ogunbiyi et al., 2011Ogunbiyi S. Chinien G. Field D. et al.Molecular characterization of dermal lymphatic endothelial cells from primary lymphedema skin.Lymphat Res Biol. 2011; 9: 19-30Crossref PubMed Scopus (9) Google Scholar). Although immunoreactivity for vascular endothelial growth factor, CD31 (blood vessel marker), and D2-40 (lymphatic vessel marker) has been described as enhanced in rosacea (Gomaa et al., 2007Gomaa A.H. Yaar M. Eyada M.M. et al.Lymphangiogenesis and angiogenesis in non-phymatous rosacea.J Cutan Pathol. 2007; 34: 748-753Crossref PubMed Scopus (78) Google Scholar), the impact of angiogenetic or vasoregulatory mechanisms appears to be irrelevant in the pathophysiology of ETR and PPR. Our combined IHC and morphometric analyses (Figure 3), together with gene array and RT-PCR studies (Figures 1 and 2), indicate that blood vessels and lymphatic vessels are dilated in ETR and PPR and that angiogenesis and lymphangiogenesis are part of the rosacea pathophysiology only in the PhR subtype (Schwab et al., 2011Schwab V.D. Sulk M. Seeliger S. et al.Neurovascular and neuroimmune aspects in the pathophysiology of rosacea.J Investig Dermatol Symp Proc. 2011; 15: 53-62Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). Flushing can be activated by the autonomic or the sensory nervous system, although both systems are no longer completely divided but communicate with each other (Gibbons et al., 2010Gibbons C.H. Wang N. Freeman R. Capsaicin induces degeneration of cutaneous autonomic nerve fibers.Ann Neurol. 2010; 68: 888-898Crossref PubMed Scopus (58) Google Scholar; Mousa et al., 2011Mousa S.A. Shaqura M. Schaper J. et al.Developmental expression of delta-opioid receptors during maturation of the parasympathetic, sympathetic, and sensory innervations of the neonatal heart: early targets for opioid regulation of autonomic control.J Comp Neurol. 2011; 519: 957-971Crossref PubMed Scopus (20) Google Scholar). The kinetics of flushing, however, resemble the pattern of sensory C-fiber activation more. Moreover, non-neuronal mediators such as lipid metabolites and tryptophan derivates are ultimately involved in vasoregulation (Wang et al., 2010Wang Y. Liu H. McKenzie G. et al.Kynurenine is an endothelium-derived relaxing factor produced during inflammation.Nat Med. 2010; 16: 279-285Crossref PubMed Scopus (283) Google Scholar). Thus, vasodilatation may be induced by neuronal stimulation, but could also result from inflammatory mediators released during the early phase of rosacea, in which inflammatory cells are already abundantly present (Figure 3; Roosterman et al., 2006Roosterman D. Goerge T. Schneider S.W. et al.Neuronal control of skin function: the skin as a neuroimmunoendocrine organ.Physiol Rev. 2006; 86: 1309-1379Crossref PubMed Scopus (397) Google Scholar; Graepel et al., 2011Graepel R. Fernandes E.S. Aubdool A.A. et al.4-Oxo-2-nonenal (4-ONE): evidence of transient receptor potential ankyrin 1-dependent and -independent nociceptive and vasoactive responses in vivo.J Pharmacol Exp Ther. 2011; 337: 117-124Crossref PubMed Scopus (44) Google Scholar). In rosacea, which is characterized by marked infiltration of T cells, macrophages, and occasionally neutrophils or B cells, an important role of blood vascular endothelial cells lies in their capacity to express selectins and cell adhesion molecules, which are important for the recruitment of leukocytes to the site of inflammation (Hua and Cabot, 2010Hua S. Cabot P.J. 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