Loffredo, S.

Marone, G.

Archivio della ricerca - Università degli studi di Napoli Federico II

LETTERS TO THE EDITORHereditary angioedema: the plasma contact system out ofcontrol: commentS . LOFFREDO*† and G . MARONE*†*Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples FedericoII; and †WAO Center of Excellence, Naples, ItalyTo cite this article: Loffredo S, Marone G. Hereditary angioedema: the plasma contact system out of control: comment. This issue, pp 2347–8.See also De Maat S, Hofman ZLM, Maas C. Hereditary angioedema: the plasma contact system out of control. J Thromb Haemost 2018;16:1674–85 and De Maat S, Hofman ZLM, Maas C. Hereditary angioedema: the plasma contact system out of control: reply. This issue,pp 2349–51.We read with great interest the elegant review entitled‘Hereditary angioedema: the plasma contact system outof control’ by De Maat et al. recently published in theJournal of Thrombosis and Haemostasis. [1]. In particular,we appreciated the section on the possible role ofangiopoietins (Angs) and vascular endothelial growth fac-tors (VEGFs) in the modulation of vascular permeabilityin patients with hereditary angioedema. The authors cor-rectly mentioned our recent article in which we identifieda substitution mutation in ANGPT1 associated withhereditary angioedema [2]. In addition, at the end of thesame paragraph, De Maat et al. discussed the possibilitythat the vasoactive mediator VEGF could contribute tothe destabilization of vascular permeability in patientswith hereditary angioedema. This hypothesis was alsoillustrated in Fig. 3 of the review, showing VEGF activat-ing VEGF receptor (VEGFR) on endothelial cells [1]. Inthe same figure, it is shown that Ang1 activates the TIE2receptor expressed on endothelial cells.We would like to highlight the complexity of theinteractions between different VEGFs and Angs andtheir receptors expressed on endothelial cells and alsoon certain immune cells. VEGF-A was initiallydiscovered and named vascular permeability factor(VPF) [3]. In fact, the group of Dvorak demonstratedthat ascites fluids from a variety of tumors and super-natants from several tumor cell lines contained anactivity (i.e. VPF) that rapidly increased microvascularpermeability. The vasodilating activity of VPF/VEGF-Ais at least 50-fold more potent than that of histamine[3].There is now compelling evidence that the VEGF familyincludes several isoforms such as VEGF-B, VEGF-C,VEGF-D, and placental growth factor, in addition toVEGF-A [4]. Moreover, there are several splicing isoformsof VEGF-A (121, 165, 189, and 206) that differ in theirbinding to matrix and specific receptors and coreceptors.For example, VEGF-A121 is acidic and freely diffusible,whereas VEGF-A165, VEGF-A189 and VEGF-A206 arebasic, and also bind to heparin and heparin proteoglycanson cellular surfaces and extracellular matrices [4]. VEGFsbind with different specificities to three mainly endothelialtransmembrane receptors, i.e. VEGFR-1, VEGFR-2, andVEGFR-3 [5]. The angiogenic and permeability activitiesof VEGF-A are mediated by interaction with VEGFR-2,whereas the lymphangiogenic activity is promoted by bind-ing to a VEGFR-2–VEGFR-3 heterodimer receptor.Additional molecules, such as Ang1 and Ang2, modu-late endothelial junctions through the engagement of twocell surface tyrosine kinase receptors, i.e. TIE1 and TIE2[6]. Ang1 is expressed by perivascular cells, such as peri-cytes, and sustains endothelial cell survival. In contrast,Ang2, which is secreted by endothelial cells, acts autocrin-ally and paracrinally as a TIE2 ligand to promote angio-genesis and vascular permeability. TIE2 is primarilyexpressed on endothelial cells and binds both Angs,whereas TIE1 is an orphan receptor that can modulateTIE2 activity.During recent years, it has become evident that sev-eral circulating (e.g. basophils, neutrophils, monocytes,Correspondence: Gianni Marone, Universita degli Studi di NapoliFederico II – Department of Translational Medical Sciences, Centerfor Basic and Clinical Immunology Research (CISI), Via Pansini, 5,Napoli 80138, ItalyTel.: +39 081 746 2271E-mail: marone@unina.itDOI: 10.1111/jth.14270Received: 9 July 2018Manuscript handled by: P. H. ReitsmaFinal decision: P. H. Reitsma, 21 July 2018© 2018 International Society on Thrombosis and HaemostasisJournal of Thrombosis and Haemostasis, 16: 2347–2351and eosinophils) and tissue-resident (e.g. macrophagesand mast cells) immune cells are important sources ofdifferent isoforms of VEGFs and Angs during inflam-mation [7–9]. More recently, we have provided the firstevidence that activated human peripheral blood neu-trophils can also release VEGF-A165b, which antagonizesthe effects of VEGF-A [9]. Collectively, the above find-ings highlight the complexity of the VEGF–VEGFRand Ang–TIE interactions between circulating immuneand endothelial cells, which may also be important inangioedema.We would like to respectfully note that our group,for the first time, demonstrated that the levels of twodifferent forms of VEGF (VEGF-A and VEGF-C) andAngs (Ang1 and Ang2) are increased in the plasma ofasymptomatic patients with hereditary angioedema ascompared with healthy controls [10]. Moreover, thelevels of VEGF-A, VEGF-C and Ang2 are alsoincreased in patients experiencing a higher number ofangioedema attacks each year. The relevance of thesefindings is supported by the correlation of plasma levelsof VEGF-A and Ang2 with those of cleaved highmolecular weight kininogen, which is a precursor ofbradykinin. In the same article, we hypothesized thatVEGFs and Angs, along with increased release of bra-dykinin, can induce a state of vascular preconditioningthat may change the threshold for the development ofangiodema attacks [10].We would like to emphasize the above findings,because the results of our study, which represented thefirst evidence that VEGFs and Angs are possibly involvedin hereditary angioedema, were not discussed in thereview by De Maat et al.AddendumBoth authors were involved in writing the article andapproved the final version to be published.Disclosure of Conflict of InterestsThe authors state that they have no conflict of interest.References1 De Maat S, Hofman ZLM, Maas C. Hereditary angioedema: theplasma contact system out of control. J Thromb Haemost 2018;16: 1674–85.2 Bafunno V, Firinu D, D’Apolito M, Cordisco G, Loffredo S,Leccese A, Bova M, Barca MP, Santacroce R, Cicardi M, DelGiacco S, Margaglione M. Mutation of the angiopoietin-1 gene(ANGPT1) associates with a new type of hereditary angioedema.J Allergy Clin Immunol 2018; 141: 1009–17.3 Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvo-rak HF. Tumor cells secrete a vascular permeability factor thatpromotes accumulation of ascites fluid. Science 1983; 219: 983–5.4 Varricchi G, Loffredo S, Galdiero MR, Marone G, CristinzianoL, Granata F, Marone G. Innate effector cells in angiogenesisand lymphangiogenesis. Curr Opin Immunol 2018; 53: 152–60.5 Varricchi G, Granata F, Loffredo S, Genovese A, Marone G.Angiogenesis and lymphangiogenesis in inflammatory skin disor-ders. J Am Acad Dermatol 2015; 73: 144–53.6 Eklund L, Saharinen P. Angiopoietin signaling in the vascula-ture. Exp Cell Res 2013; 319: 1271–80.7 de Paulis A, Prevete N, Fiorentino I, Rossi FW, Staibano S,Montuori N, Ragno P, Longobardi A, Liccardo B, Genovese A,Ribatti D, Walls AF, Marone G. Expression and functions ofthe vascular endothelial growth factors and their receptors inhuman basophils. J Immunol 2006; 177: 7322–31.8 Granata F, Frattini A, Loffredo S, Staiano RI, Petraroli A,Ribatti D, Oslund R, Gelb MH, Lambeau G, Marone G, Trig-giani M. Production of vascular endothelial growth factors fromhuman lung macrophages induced by group IIA and group Xsecreted phospholipases A2. J Immunol 2010; 184: 5232–41.9 Loffredo S, Borriello F, Iannone R, Ferrara AL, Galdiero MR,Gigantino V, Esposito P, Varricchi G, Lambeau G, CassatellaMA, Granata F, Marone G. Group V secreted phospholipase A2induces the release of proangiogenic and antiangiogenic factorsby human neutrophils. Front Immunol 2017; 8: 443–53.10 Loffredo S, Bova M, Suffritti C, Borriello F, Zanichelli A, Petrar-oli A, Varricchi G, Triggiani M, Cicardi M, Marone G. Elevatedplasma levels of vascular permeability factors in C1 inhibitor-defi-cient hereditary angioedema. Allergy 2016; 71: 989–96.© 2018 International Society on Thrombosis and Haemostasis2348 Letters to the Editor

Hereditary angioedema: the plasma contact system out of control: comment

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Hereditary angioedema: the plasma contact system out of control: comment

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