A literature review of microvascular proliferation in arteriovenous malformations of skin and soft tissue

Background and aim: Arteriovenous malformations (AVM) are defined as being quiescent vascular masses composed of mature vessels. However, recent studies reported areas of microvascular proliferation (MVP) in AVM, indicating a process of angiogenesis. As this finding questions the previous definition, the primary objective of this review was to evaluate whether angiogenesis occurs in vascular malformations of skin and soft tissue, and secondly, to identify potential factors involved in MVP.
Method: Due to the multifaceted nature of this subject, a hermeneutic methodology was used to select articles that were likely to provide a deeper understanding of MVP in vascular malformations. Through citation tracking and database searching in PubMed and Web of Science, relevant articles were identified. All study designs concerning occurrence of MVP in AVM of skin and soft tissue in all age groups were included. The Newcastle-Ottawa scale was used for quality assessment.
Results: 16 studies were included in this review which reported occurrence of MVP areas in between the otherwise mature vessels of vascular malformations. In these studies, angiogenesis was reported only in AVM-type of vascular malformations. Increased levels of pro-angiogenic factors were also reported and proliferation was found most prominently during adolescence. Finally, several types of hormone receptors also have been described in tissues of AVM.
Conclusion: Overall, the reviewed data support occurrence of active angiogenesis, highlighted by the presence of MVP in the arteriovenous type of vascular malformations, and a possible concurrent lesion progression towards a higher Schobinger stage of clinical severity. The relative scarcity of data at present implies that further research is required to elucidate the nature of MVP in AVM, which could have implications for developing targeted pharmacotherapy.
Relevance for patients: Active angiogenesis caused by MVP in AVM patients is known to be correlating to clinical symptoms and contributing to the progression of the disease, recurrence rate, and patient’s quality of life.
[1] Mulliken JB, Glowacki J. Hemangiomas and Vascular Malformations in Infants and Children. Plast Reconstr Surg 1982;69:421-2.
[2] Enjolras O. Classification and Management of the Various Superficial Vascular Anomalies: Hemangiomas and Vascular Malformations.J Dermatol 1997;24:701-10.
[3] Greene AK, Liu AS, Mulliken JB, Chalache K, Fishman SJ. Vascular Anomalies in 5,621 Patients: Guidelines for Referral.J Pediatr Surg 2011;46:1784-9.
[4] Meijer-Jorna LB, van der Loos CM, de Boer OJ, van der Horst CM, van der Wal AC. Microvascular Proliferation in Congenital Vascular Malformations of Skin and Soft Tissue.J Clin Pathol 2007;60:798-803.
[5] Mcinnes RR. Developmental Biology: Frontiers for Clinical Genetics Vascular Malformations: Localized Defects in Vascular Morphogenesis.J Cell Physiol 2003;63:340-51.
[6] Greene AK, Orbach DB. Management of ARTERIOVENOUS malformations. Clin Plast Surg 2011;38:95-106.
[7] Finn MC, Glowacki J, Mulliken JB. Congenital Vascular Lesions: Clinical Application of a New Classification.J Pediatr Surg 1983;18:894-900.
[8] Merrow AC, Gupta A, Patel MN, Adams DM. 2014 Revised Classification of Vascular Lesions from the International Society for the Study of Vascular Anomalies: RadiologicPathologic Update. Radiographics 2016;36:1494-516.
[9] International Society for the Study of Vascular Anomalies (ISSVA). ISSVA Classification for Vascular Anomalies. Melbourne: ISSVA; 2018 Available from: https://www. issva.org/classification. Last accessed on 2021 Mar 30.
[10] Wassef M, Blei F, Adams D, Alomari A, Baselga E, Berenstein A, et al. Vascular Anomalies Classification: Recommendations from the International Society for the Study of Vascular Anomalies. Pediatrics 2015;136:e203-14.
[11] Redondo P, Martínez-Cuesta A, Quetglas EG, Idoate M. Active Angiogenesis in an Extensive Arteriovenous Vascular Malformation:A Possible Therapeutic Target? Arch Dermatol 2007;143:1043-5.
[12] Boell SK, Cecez-Kecmanovic D. Literature Reviews and the Hermeneutic Circle. Aust Acad Res Libr 2010;41:129-44.
[13] Wells GA, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. Newcastle-Ottawa Quality Assessment Scale. Ottawa, Canada: Ottawa Hospital Research Institute; 2014. p. 2-4.
[14] Liu AS, Mulliken JB, Zurakowski D, Fishman SJ, Greene AK. Extracranial Arteriovenous Malformations: Natural Progression and Recurrence after Treatment. Plast Reconstr Surg 2010;125:1185-94.
[15] Marler JJ, Fishman SJ, Kilroy SM, Fang J, Upton J, Mulliken JB, et al. Increased Expression of Urinary Matrix Metalloproteinases Parallels the Extent and Activity of Vascular Anomalies. Pediatrics 2005;116:38-45.
[16] Meijer-Jorna LB, van der Loos CM, Teeling P, de Boer OJ, Florquin S, van der Horst CM, et al. Proliferation and Maturation of Microvessels in Arteriovenous Malformations-Expression Patterns of Angiogenic and Cell Cycle-Dependent Factors.J Cutan Pathol 2012;39:610-20.
[17] Lu L, Bischoff J, Mulliken JB, Bielenberg DR, Fishman SJ, Greene AK. Increased Endothelial Progenitor Cells and Vasculogenic Factors in Higher-Staged Arteriovenous Malformations. Plast Reconstr Surg 2011;128:260-9.
[18] Pavlov KA, Gershtein ES, Dubova EA, Shchegolev AI. Vascular endothelial growth factor and Type 2 receptor for this factor in vascular malformations. Bull Exp Biol Med 2011;150:481-4.
[19] Pavlov KA, Dubova EA, Shchyogolev AI, Mishnyov OD. Expression of Growth Factors in Endotheliocytes in Vascular Malformations. Bull Exp Biol Med 2009;147:366-70.
[20] Rothbart D, Awad IA, Lee J, Kim J, Harbaugh R, Criscuolo GR. Expression of Angiogenic Factors and Structural Proteins in Central Nervous System Vascular Malformations. Neurosurgery 1996;38:915-22.
[21] Kiliç T, Pamir N, Küllü S, Eren F, Ozek MM, Black PM. Expression of Structural Proteins and Angiogenic Factors in Cerebrovascular Anomalies. Neurosurgery 2000;46:1179-92.
[22] Ryu JY, Kim YH, Lee JS, Lee JW, Oh EJ, Kim HM, et al. Oscillatory Shear Stress Promotes Angiogenic Effects in Arteriovenous Malformations Endothelial Cells. Mol Med 2021;27:31.
[23] Wautier MP, Boval B, Chappey O, Enjolras O, Wernert N, Merland JJ, et al. Cultured Endothelial Cells from Human Arteriovenous Malformations Have Defective Growth Regulation. Blood 1999;94:2020-8.
[24] Dawson P, Kennedy A, Petty RG. Absence of an Angiogenic Factor in Large Systemic Arteriovenous Malformation. Invest Radiol 1993;28:594-7.
[25] Maclellan RA, Vivero MP, Purcell P, Purcell P, Kozakewich HP, DiVasta AD, et al. Expression of FollicleStimulating Hormone Receptor in Vascular Anomalies. Plast Reconstr Surg 2014;133:344e-51e.
[26] Kulungowski AM, Hassanein AH, Nosé V, Fishman SJ, Mulliken JB, Upton J, et al. Expression of Androgen, Estrogen, Progesterone, and Growth Hormone Receptors in Vascular Malformations. Plast Reconstr Surg 2012;129:919-24.
[27] Duyka LJ, Fan CY, Coviello-Malle JM, Buckmiller L, Suen JY. Progesterone Receptors identified in Vascular Malformations of the Head and Neck. Otolaryngol Head Neck Surg 2009;141:491-5.
[28] Meijer-Jorna LB, van der Loos CM, de Boer OJ, Horrevoets AJ, Mekkes JR, van der Horst CM, et al. Microvascular Proliferations in Arteriovenous Malformations Relate to High-Flow Characteristics,Inflammation, and Previous Therapeutic Embolization of the Lesion.J Am Acad Dermatol 2013;68:638-46.
[29] Zhan M, Hori Y, Wada N, Ikeda J, Hata Y, Osuga K, et al. Angiogenic Factor with G-Patch and FHA Domain 1 (AGGF1) Expression in Human Vascular Lesions. Acta Histochem Cytochem 2016;49:75-81.
[30] Timbang MR, Richter GT. Update on Extracranial Arteriovenous Malformations:A Staged Multidisciplinary Approach. Semin Pediatr Surg 2020;29:150965.
[31] Kubis N, Levy BI. Understanding Angiogenesis:A Clue for Understanding Vascular Malformations.J Neuroradiol 2004;31:365-8.
[32] Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, et al. VEGF Guides Angiogenic Sprouting Utilizing Endothelial Tip Cell Filopodia.J Cell Biol 2003;161:1163-77.
[33] Chen GZ, Ke Y, Qin K, Dong MQ, Zeng SJ, Lin XF, et al. Analysis of the Expression of AngioarchitectureRelated Factors in Patients with Cerebral Arteriovenous Malformation. Chin Med J (Engl) 2017;130:2465-72.
[34] Koizumi T, Shiraishi T, Hagihara N, Tabuchi K, Hayashi T, Kawano T. Expression of Vascular Endothelial Growth Factors and their Receptors in and Around Intracranial Arteriovenous Malformations. Neurosurgery 2002;50:117-24.
[35] Sure U, Butz N, Schlegel J, Siegel AM, WakatJP, MennelHD, et al. Endothelial Proliferation, Neoangiogenesis, and Potential De Novo Generation of Cerebrovascular Malformations.J Neurosurg 2001;94:972-7.
[36] Hashimoto T, Lam T, Boudreau NJ, Bollen AW, Lawton MT, Young WL. Abnormal Balance in the AngiopoietinTie2 System in Human Brain Arteriovenous Malformations. Circ Res 2001;89:111-3.
[37] Hashimoto T, Young WL. Roles of Angiogenesis and Vascular Remodeling in Brain Vascular Malformations. Semin Cerebrovasc Dis Stroke 2004;4:217-25.
[38] Pulkkinen HH, Kiema M, Lappalainen JP, Toropainen A, Beter M, Tirronen A, et al. BMP6/TAZ-Hippo Signaling Modulates Angiogenesis and Endothelial cell Response to VEGF. Angiogenesis 2021;24:129-44.
[39] Mancini ML, Terzic A, Conley BA, Oxburgh LH, Nicola T, Vary CP. Endoglin Plays Distinct Roles in Vascular Smooth Muscle Cell Recruitment and Regulation of Arteriovenous Identity During Angiogenesis. Dev Dyn 2009;238:2479-93.
[40] Sainson RCA, Johnston DA, Chu HC, Holderfield MT, Nakatsu MN, Crampton SP, et al. TNF Primes Endothelial Cells for Angiogenic Sprouting by Inducing a Tip Cell Phenotype. Blood 2008;111:4997-5007.
[41] Zhang T, Yao Y, Wang J, Li Y, He P, Pasupuleti V, et al. Haploinsufficiency of Klippel-Trenaunay Syndrome gene Aggf1 Inhibits Developmental and Pathological Angiogenesis by Inactivating PI3K and AKT and Disrupts Vascular Integrity by Activating VE-Cadherin. Hum Mol Genet 2016;25:5094-110.
[42] Castel P, Carmona FJ, Grego-Bessa J, Berger MF, Viale A, Anderson KV, et al. Somatic PIK3CA Mutations as a Driver of Sporadic Venous Malformations. Sci Transl Med 2016;8:332ra42.
[43] Wei T, Zhang H, Cetin N, Miller E, Moak T, Suen JY, et al. Elevated Expression of Matrix Metalloproteinase-9 not Matrix Metalloproteinase-2 Contributes to Progression of Extracranial Arteriovenous Malformation. Sci Rep 2016;6:24378.
[44] Cianfarani S. Is High-Dose Growth Hormone Treatment during Puberty Worthwhile? Horm Res Paediatr 2014;82:143-4.
[45] Clapp C, Thebault S, Jeziorski MC, Martínez De La Escalera G. Peptide Hormone Regulation of Angiogenesis. Physiol Rev 2009;89:1177-215.
[46] de Lima CF, dos Santos Reis MD, da Silva Ramos FW, Ayres-Martins S, Smaniotto S. Growth Hormone Modulates In Vitro Endothelial Cell Migration and Formation of Capillary-Like Structures. Cell Biol Int 2017;41:577-84.
[47] Papadimitriou K, Kountourakis P, Kottorou AE, Antonacopoulou AG, Rolfo C, Peeters M, et al. FollicleStimulating Hormone Receptor (FSHR):A Promising Tool in Oncology? Mol Diagn Ther 2016;20:523-30.
[48] Sieveking DP, Lim P, Chow RW Dunn LL, Bao S, McGrath KC,et al. A Sex-Specific Role for Androgens in Angiogenesis.J Exp Med 2010;207:345-52.
[49] Losordo DW, Isner JM. Estrogen and Angiogenesis:A Review. Arterioscler Thromb Vasc Biol2001;21:6-12.
[50] Lee PA, Xenakis T, Winer J, Matsenbaugh S. Puberty in Girls: Correlation of Serum Levels of Gonadotropins, Prolactin, Androgens, Estrogens, and Progestins with Physical Changes.J Clin Endocrinol Metab 1976;43:775-84.
[51] Chen Y, Zhu W, Bollen AW, Lawton MT, Barbaro NM, Dowd CF, et al. Evidence of Inflammatory Cell Involvement in Brain Arteriovenous Malformations. Neurosurgery 2008;62:1340-9.
[52] Nissinen L, Kähäri VM. Matrix Metalloproteinases in Inflammation. Biochim Biophys Acta 2014;1840:2571-80.
[53] Krock BL, Skuli N, Simon MC. Hypoxia-Induced Angiogenesis: Good and Evil. Genes Cancer 2011;2:1117-33.
[54] Hashimoto T, Wen G, Lawton MT, Boudreau NJ, Bollen AW, Yang GY, et al. Abnormal Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Brain Arteriovenous Malformations. Stroke 2003;34:925-30.
[55] Lim CS, Kiriakidis S, Sandison A, Paleolog EM, Davies AH. Hypoxia-Inducible Factor Pathway and Diseases of the Vascular Wall.J Vasc Surg 2013;58:219-30.
[56] Takagi Y, Kikuta K, Moriwaki T, Aoki T, Nozaki K, Hashimoto N, et al. Expression of Thioredoxin-1 and Hypoxia Inducible Factor-1α in Cerebral Arteriovenous Malformations: Possible Role of Redox Regulatory Factor in Neoangiogenic Property. Surg Neurol Int 2011;2:61.
[57] Ng I, Tan WL, Ng PY, Lim J. Hypoxia Inducible Factor-1 Alpha and Expression of Vascular Endothelial Growth factor and its Receptors in Cerebral Arteriovenous Malformations.J Clin Neurosci 2005;12:794-9.
[58] Gao P, Zhu Y, Ling F, Shen F, Lee B, Gabriel RA, et al. Nonischemic Cerebral Venous Hypertension Promotes a Pro-Angiogenic Stage through HIF-1 Downstream Genes and Leukocyte-Derived MMP-9.J Cereb Blood Flow Metab 2009;29:1482-90.
[59] Tan HH, Ge ZZ, Gao YJ, Chen HM, Fang JY, Chen HY, et al. The role of HIF-1, Angiopoietin-2, Dll4 and Notch1 in Bleeding Gastrointestinal Vascular Malformations and Thalidomide-Associated Actions:A Pilot In Vivo Study.J Dig Dis 2011;12:349-56.
[60] Buell TJ, Ding D, Starke RM, Webster Crowley R, Liu KC. Embolization-Induced Angiogenesis in Cerebral Arteriovenous Malformations.J Clin Neurosci 2014;21:1866-71.
[61] Smits PJ, Konczyk DJ, Sudduth CL, Goss JA, Greene AK. Endothelial MAP2K1 Mutations in Arteriovenous Malformation Activate the RAS/MAPK Pathway. Biochem Biophys Res Commun 2020;529:450-4.
[62] Nikolaev SI, Vetiska S, Bonilla X, Boudreau E, Jauhiainen S, Rezai Jahromi B, et al. Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.N Engl J Med 2018;378:250-61.
[63] Priemer DS, Vortmeyer AO, Zhang S, Chang HY, Curless KL, Cheng L. Activating KRAS Mutations in Arteriovenous Malformations of the Brain: Frequency and Clinicopathologic Correlation. Hum Pathol 2019;89:33-9.
[64] Guo Y, Pan W, Liu S, Shen ZF, Xu Y, Hu LL. ERK/MAPK Signalling Pathway and Tumorigenesis (Review). Exp Ther Med 2020;19:1997-2007.
[65] Boon LM, Ballieux F, Vikkula M. Pathogenesis of Vascular Anomalies. Clin Plast Surg 2011;38:7-19.
[66] Jin Y, Muhl L, Burmakin M, Wang Y, Duchez AC, Betsholtz C, et al. Endoglin Prevents Vascular Malformation by Regulating Flow-Induced Cell Migration and Specification Through VEGFR2 Signalling. Nat Cell Biol 2017;19:639-52.
[67] Revencu N, Boon LM, Mendola A, Cordisco MR, Dubois J, Clapuyt P, et al. RASA1 Mutations and Associated Phenotypes in 68 Families with Capillary MalformationArteriovenous Malformation. Hum Mutat 2013;34:1632-41.
[68] Li Y, Chen H. Novel EPHB4 Mutation in Capillary Malformation-Arteriovenous Malformation Syndrome 2 (CM-AVM2): The First Genetic Study in Asians; 2020. p. 1-9.
[69] Vernimmen FJ. Vascular Endothelial Growth Factor Blockade:A Potential New Therapy in the Management of Cerebral Arteriovenous Malformations.J Med Hypotheses Ideas 2014;8:57-61.
[70] Ota T, Komiyama M. Pathogenesis of Non-Hereditary Brain Arteriovenous Malformation and Therapeutic Implications. Interv Neuroradiol 2020;26:244-53.