https://doi.org/10.4081/btvb.2025.152
Vasculopathy: a possible factor affecting hereditary angioedema
Submitted: 25 July 2024
Accepted: 9 January 2025
Published: 4 February 2025
Accepted: 9 January 2025
Abstract Views: 4
PDF: 4
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Hereditary angioedema (HAE) is a rare genetic disorder that causes swelling of tissues in the hands, feet, limbs, face, intestinal tract, or airway. The SERPING1 gene, encoding the C1-INH, determines the wide range of clinical symptoms associated with CI-INH deficient HAE. C1-INH regulates enzymes involved in bradykinin production, leading to increased vascular permeability and angioedema. The most prevalent cause of this condition is either a deficiency or dysfunction of C1-INH. A subset of patients exhibits a third form of HAE (nC1-INH-HAE). This clinical subtype, distinguished by the absence of mutations in SERPING1, has a clinical picture similar to C1-INH-HAE but with normal C1-INH level and activity. This review summaries recent progress in genetic characterization of angioedema and discusses future potential for identifying additional genetic abnormalities in HAE. The elucidation of mechanisms leading to HAE could contribute to better understanding of the endothelial cell physiopathology.
1. Kaplan, A.P. Angioedema. World Allergy Organ J 2008;1:103-13.
DOI: https://doi.org/10.1097/WOX.0b013e31817aecbe
2. Wedner HJ. Hereditary angioedema: Pathophysiology (HAE type I, HAE type II, and HAE nC1-INH) Allergy Asthma Proc 202041:S14-7.
DOI: https://doi.org/10.2500/aap.2020.41.200081
3. Cicardi M, Zuraw BL. Angioedema due to bradykinin dysregulation. J Allergy Clin Immunol Pract 2018;6:1132-41.
DOI: https://doi.org/10.1016/j.jaip.2018.04.022
4. Ghazi A, Grant JA. Hereditary angioedema: Epidemiology, management, and role of icatibant. Biologics 2013;7:103-13.
DOI: https://doi.org/10.2147/BTT.S27566
5. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: A broad review for clinicians. Arch Intern Med 2001;161:2417-29.
DOI: https://doi.org/10.1001/archinte.161.20.2417
6. Bove M, Schiavone S, Tucci P, et al. Ketamine administration in early postnatal life as a tool for mimicking autism spectrum disorders core symptoms. Prog Neuropsychopharmacol Biol 2022;117:110560.
DOI: https://doi.org/10.1016/j.pnpbp.2022.110560
7. Santacroce R, D’Andrea G, Maffione AB, et al. The genetics of hereditary angioedema: a review. Clin Med 2021;10:2023.
DOI: https://doi.org/10.3390/jcm10092023
8. Mormile I , Palestra F, Petraroli A, et al. Neurologic and psychiatric manifestations of bradykinin-mediated angioedema: old and new challenges Int J Mol Sci 2023;24:12184.
DOI: https://doi.org/10.3390/ijms241512184
9. Joseph K, Kaplan AP. Formation of bradykinin: a major contributor to the innate inflammatory response. Adv Immunol 2005;86:159-208.
DOI: https://doi.org/10.1016/S0065-2776(04)86005-X
10. Giardino I, D'Apolito M, Brownlee M, et al. Vascular toxicity of urea, a new "old player" in the pathogenesis of chronic renal failure induced cardiovascular diseases. Turk Pediatri Ars 2017;52:187-93.
DOI: https://doi.org/10.5152/TurkPediatriArs.2017.6314
11. Prado GN, Taylor L, Zhou X, et al. Mechanisms regulating the expression, self-maintenance and signalling function of the bradykinin B2 and B1 receptors. J Cell Physiol 2002;193:275-86.
DOI: https://doi.org/10.1002/jcp.10175
12. Csuka D, Veszeli N, Varga L, et al. The role of the complement system in hereditary angioedema. Mol Immunol 2017;89:59-68.
DOI: https://doi.org/10.1016/j.molimm.2017.05.020
13. Davis AE III. The pathophysiology of hereditary angioedema. Clin Immunol 2005;114:3-9.
DOI: https://doi.org/10.1016/j.clim.2004.05.007
14. Bork K, Barnstedt S-E, Koch P, Traupe H. Hereditary angioedema with normal C1-inhibitor activity in women. Lancet 2000;356:213-7.
DOI: https://doi.org/10.1016/S0140-6736(00)02483-1
15. Binkley KE, Davis A III. Clinical, biochemical, and genetic characterization of a novel estrogen-dependent inherited form of angioedema. J Allergy Clin Immunol 2000;106:546-50.
DOI: https://doi.org/10.1067/mai.2000.108106
16. Kaplan AP, Greaves MW. Angioedema. J Am Acad Dermatol 2005;53:373-88.
DOI: https://doi.org/10.1016/j.jaad.2004.09.032
17. Morgese MG, Bove M, Di Cesare Mannelli L, et al. Precision medicine in Alzheimer’s disease: investigating comorbid common biological substrates in the rat model of amyloid beta-induced toxicity. Front Pharm 2022;12:799561.
DOI: https://doi.org/10.3389/fphar.2021.799561
18. Zuraw BL. Hereditary angioedema with normal C1 inhibitor: Four types and counting. Allergy Clin Immunol 2018;141:884-5.
DOI: https://doi.org/10.1016/j.jaci.2018.01.015
19. Caccia S, Suffritti C, Carzaniga T, et al. Intermittent C1-inhibitordeficiency associated with recessive inheritance: Functional and structural insight. Sci Rep 2018;8:977.
DOI: https://doi.org/10.1038/s41598-017-16667-w
20. Kalmár L, Hegedüs T, Farkas H, et al. HAEdb: A novel interactive, locus-specific mutation database for the C1 inhibitor gene. Human Mutat 2005;25:1-5.
DOI: https://doi.org/10.1002/humu.20112
21. Bors A, Csuka D, Varga L, et al. Less severe clinical manifestations in patients with hereditary angioedema with missense C1INH gene mutations. J. Allergy Clin. Immunol 2003;131:1708-11.
DOI: https://doi.org/10.1016/j.jaci.2012.11.015
22. Dewald G, Bork K. Missense mutations in the coagulation factor XII (Hageman factor) gene in hereditary angioedema with normal C1 inhibitor. Biochem Biophys Res Commun 2006;343:1286-9.
DOI: https://doi.org/10.1016/j.bbrc.2006.03.092
23. Khan S, Longhurst H. Epigenetic alterations on C1-inhibitor expression may influence hereditary angioedema attack frequency and C4 levels. Clin Exp Immunol 2020;202:144-5.
DOI: https://doi.org/10.1111/cei.13516
24. Vatsiou S, Zamanakou M, Loules G, et al. A novel deep intronic SERPING1 variantas a cause of hereditary angioedema due to C1-inhibitor deficiency. Allergol Int 2020;69:443-9.
DOI: https://doi.org/10.1016/j.alit.2019.12.009
25. Bork K, Wulff K, Meinke P, et al. A novel mutation in the coagulation factor 12 gene in subjects with hereditary angioedema and normal C1-inhibitor. Clin Immunol 2011;141:31-5.
DOI: https://doi.org/10.1016/j.clim.2011.07.002
26. Bork K, Wulff K, Steinmüller-Magin L, et al. Hereditary angioedema with a mutation in the plasminogen gene. Allergy 2018;73:442-50.
DOI: https://doi.org/10.1111/all.13270
27. Bafunno V, Firinu D, D’Apolito M, et al. Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema. J Allergy Clin Immunol 2018;141:1009-17.
DOI: https://doi.org/10.1016/j.jaci.2017.05.020
28. Bork K, Wulff K, Rossmann H, et al. Hereditary angioedema cosegregating with a novel kininogen 1 gene mutation changing the N-terminal cleavage site of bradykinin. Allergy 2019;74:2479-81.
DOI: https://doi.org/10.1111/all.13869
29. Ariano A, D’Apolito M, Bova M, et al. A myoferlin gain-of-function variant associates with a new type of hereditary angioedema. Allergy 2020;75:2989-92.
DOI: https://doi.org/10.1111/all.14454
30. Bork K, Wulff K, Möhl B, et al. Novel hereditary angioedema linked with a heparan sulfate 3-O-sulfotransferase 6 gene mutation. J Allergy Clin Immunol 2021;148:1041-8.
DOI: https://doi.org/10.1016/j.jaci.2021.01.011
31. D'Apolito M, Santacroce R, Josviack D, et al. DAB2IP associates with hereditary angioedema: insights into the role of VEGF signaling in HAE pathophysiology. J Allergy Clin Immunol 2024;154:698-706.
DOI: https://doi.org/10.1016/j.jaci.2024.05.017
32. Maas C. Plasm inflammation-an emerging pathway to bradykinin production. Front Immunol 2019;10:2046.
DOI: https://doi.org/10.3389/fimmu.2019.02046
33. Cichon S, Martin L, Hennies HC, et al. Increased activity of coagulation factor XII (Hageman factor) causes hereditary angioedema type III. Am J Hum Genet 2006;79:1098-104.
DOI: https://doi.org/10.1086/509899
34. Bork K, Kleist R, Hardt J, Witzke G. Kallikrein-kinin system and fibrinolysis in hereditary angioedema due to factor XII gene mutation Thr309Lys. Blood Coag Fibrinol 2009;20:325-32.
DOI: https://doi.org/10.1097/MBC.0b013e32832811f8
35. Bork K, Wulff K, Witzke G, et al. Tamoxifen may cause life-threatening angioedema attacks in patients with hereditary angioedema. J Eur Acad Dermatol Venereol 2017;31:e237-9.
DOI: https://doi.org/10.1111/jdv.14056
36. Dewald G. A missense mutation in the plasminogen gene, within the plasminogen kringle 3 domain, in hereditary angi-oedema with normal C1 inhibitor. Biochem Biophys Res Commun 2018;498:193-8.
DOI: https://doi.org/10.1016/j.bbrc.2017.12.060
37. d'Apolito M, Santacroce R, Colia AL, et al. Angiopoietin‐1 haploinsufficiency affects the endothelial barrier and causes hereditary angioedema. Clin Exp Allergy 2019;49:626-35.
DOI: https://doi.org/10.1111/cea.13349
38. D'Apolito M, Colia AL, Manca E, et al. Urea memory: transient cell exposure to urea causes persistent mitochondrial ROS production and endothelial dysfunction. Toxins 2018;10:410.
DOI: https://doi.org/10.3390/toxins10100410
39. Cagini N, Veronez CL, Azevedo BF, et al. In silico analysis of Alterations in ANGPT1 gene supports a new pathway responsible to mediate hereditary angioedema in Brazilian patients with no mutations in SERPING1 and F12 genes. J Allergy Clin Immunol 2018;141:AB46.
DOI: https://doi.org/10.1016/j.jaci.2017.12.150
40. Hujová P, Souček P, Grodecká L, et al. Deep intronic mutation inSERPING1 caused hereditary angioedema through pseudoexon activation. J Clin Immunol 2020;40:435-46.
DOI: https://doi.org/10.1007/s10875-020-00753-2
41. Veronez CL, Aabom A, Martin RP, et al. Genetic variation of Kallikrein-Kinin system and related genes in patients with hereditary angioedema. Front Med 2019;6:6-28.
DOI: https://doi.org/10.3389/fmed.2019.00028
42. Germenis AE, Margaglione M, Pesquero JB, et al. International consensus on the use of genetics in the management of hereditary angioedema. J Allergy Clin. Immunol Pract 2020;8:901-11.
43. Radeva MY, WaschkeJ. Mind the gap: Mechanisms regulating the endothelial barrier. Acta Physiol Oxf 2018;222:e12860
DOI: https://doi.org/10.1111/apha.12860
44. Komarova YA, Kruse, K, Mehta D, Malik AB. Protein interactions at endothelial junctions and signaling mechanisms regulating endothelial permeability. Circ Res 2017;1201:79-206.
DOI: https://doi.org/10.1161/CIRCRESAHA.116.306534
45. D’Apolito M, D’Andrea G, Colia AL, et al. The molecular organization of endothelial junctions in vascular permeability. EuroMediterranean Biomed J 2021;16:108-13.
46. Gavard J, Patel V, Gutkind JS. Angiopoietin-1 prevents VEGF-induced endothelial permeability by sequestering Src through mDia. Dev Cell 2008;14:25-36.
DOI: https://doi.org/10.1016/j.devcel.2007.10.019
47. Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 2002;1:219-27.
DOI: https://doi.org/10.1016/S1535-6108(02)00051-X
48. Autiero M, Waltenberger J, Communi D, et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 2003;9:936-43.
DOI: https://doi.org/10.1038/nm884
49. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signaling in control of vascular function. Nat Rev Mol Cell Biol 2006;7:359-71.
DOI: https://doi.org/10.1038/nrm1911
50. Xie Z, Ghosh CC, Patel R, et al. Vascular endothelial hyperpermeability induces the clinical symptoms of Clarkson disease (the systemic capillary leak syndrome). Blood 2012;119:4321-32.
DOI: https://doi.org/10.1182/blood-2011-08-375816
51. Van der Flier M, van Leeuwen HJ, van Kessel KP, et al. Plasma vascular endothelial growth factor in severe sepsis. Shock 2005;23:35-8.
DOI: https://doi.org/10.1097/01.shk.0000150728.91155.41
52. Margaglione M, D’Apolito M, Santocroce R, Maffione AB. Hereditary angioedema: looking for bradykinin production and triggers of vascular permeability Clin Exp Allergy 2019;49:1395-402.
DOI: https://doi.org/10.1111/cea.13506
53. Jones D, Zafra H, Anderson J. Managing diagnosis, treatment, and burden of disease in hereditary angioedema patients with normal C1-esterase inhibitor. J Asthma Allergy 2023;16:447-60.
DOI: https://doi.org/10.2147/JAA.S398333
How to Cite
Colia, A. L., Ranaldi, A., Santacroce, R., D’Andrea, G., Maffione, A. B., Margaglione, M., & D’Apolito, M. (2025). Vasculopathy: a possible factor affecting hereditary angioedema. Bleeding, Thrombosis and Vascular Biology, 4(1). https://doi.org/10.4081/btvb.2025.152
Copyright (c) 2025 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Boris Shenkman, Ivan Budnik, Yulia Einav, Interaction between adenosine diphosphate receptors and protein-kinase C isoforms in platelet adhesion under flow condition , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 1 (2023)
- Jingnan Huang, Delia I. Fernández, Jinmi Zou, Xueqing Wang, Johan W.M. Heemskerk, Ángel García, Restrained glycoprotein VI-induced platelet signaling by tyrosine protein phosphatases independent of phospholipase Cγ2 , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 3 (2023)
- Massimo Franchini, Daniele Focosi, The changing landscape of treatment for acquired hemophilia A , Bleeding, Thrombosis and Vascular Biology: Vol. 4 No. 1 (2025)
- Loredana Bury, Paolo Gresele, The amazing genetic complexity of anucleated platelets , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 2 (2022)
- Robert Parambi, Nicole Ziliotto, Francesco Bernardi , Marcello Baroni , Richard W Browne , Dejan Jakimovski, Bianca Weinstock-Guttman, Robert Zivadinov, Murali Ramanathan, Crosstalk between hemostasis inhibitors and cholesterol biomarkers in multiple sclerosis , Bleeding, Thrombosis and Vascular Biology: Vol. 1 No. 3 (2022)
- Mattia Galli, C. Michael Gibson, Dominick J. Angiolillo, Factor XI inhibitors in adjunct to antiplatelet therapy: the ultimate dual-pathway inhibition? , Bleeding, Thrombosis and Vascular Biology: Vol. 2 No. 3 (2023)
- Lisa Pieri, Silvia Linari, Francesca Salvianti, Monica Attanasio, Giancarlo Castaman, Impaired platelet function in Hermansky-Pudlak syndrome associated with novel mutations in HPS3, HPS6 and HPS8 genes , Bleeding, Thrombosis and Vascular Biology: Vol. 3 No. 3 (2024)
You may also start an advanced similarity search for this article.
