Molecular Genetics of Vascular Malformations


Vascular anomalies are separated into vascular tumours and vascular malformations. Vascular malformations are named according to the affected type of vessels, that is venous, capillary, arteriovenous or lymphatic malformations. Up to now, sclerotherapy, embolisation and/or surgery are the treatments of choice, yet they do not often offer a curative treatment. Thus, there is an important need to develop novel disease‐specific therapeutic approaches.

Inherited forms of vascular malformations led to the identification of several genes that are mutated encoding dysfunctional proteins. Demonstration that tissular second hits are commonly involved in inherited forms to explain development of lesions led to study somatic mutations in sporadically occurring forms. Since the primary discovery demonstrating that venous malformations are due to somatic mutations in TIE2/TEK, most types of vascular anomalies now have a known genetic cause. Thereby, the signalling pathways involved have been unravelled, leading to a better understanding of the aetiopathogenesis of vascular anomalies. As – like in cancers – the RAS/MAPK/ERK and the PI3K/AKT/mTOR signalling are enhanced in most vascular anomalies, treatment with cancer drugs interfering with these pathways could represent novel treatment options.

Key Concepts

  • Vascular anomalies are classified into tumours and malformations. The latter are further divided according to the affected vessels to capillary, venous, arterial, lymphatic and combined malformations.
  • Treatment options are mostly restricted to sclerotherapy, embolisation and/or surgery.
  • Most vascular anomalies are caused by genetic mutations, either germ line or somatic.
  • Altered signalling involves RAS/MAPK/ERK, BMP9/10/ALK, PI3K/AKT/mTOR and VEGF/VEGFR3 pathways.
  • Same pathways are also involved in cancers. Making repurposing of cancer drugs that interfere with these pathways, such as the mTOR inhibitor rapamycin, of interest for the treatment of vascular anomalies.

Keywords: haemangioma; malformation; vascular; gene; mutation; RAS/MAPK/ERK signalling; PI3K/AKT/mTOR signalling; rapamycin; inhibitor; repurposing

Figure 1. Images of vascular tumours and vascular malformations. (a) Voluminous haemangioma on the summit of the skull of a baby. (b) Hemifacial capillary malformation. (c) Characteristic capillary malformation of ‘CM‐AVM’: oval and light‐red appearance. Arrowheads indicate a pale halo around the malformation. (d) Arteriovenous malformation in an 8‐year‐old boy initially diagnosed as an infantile haemangioma. The lesion was warm and a thrill is felt on palpation. (e) Arteriography demonstrates abnormal vasculature. (f) Cerebral CT scan of a patient presenting cerebral cavernous malformation (arrowheads). (g) Characteristic glomuvenous malformations on the arm (arrow) and the leg (arrowhead) of a young boy. Note the nodular appearance and bluish‐purple colouration. (h) Venous malformations of the lips. Note their homogenous aspect and bluish colouration. (i) Subcutaneous lymphatic malformation on the axilla (arrows).
Figure 2. VEGFR2 signalling involved in IH. Variants in TEM8 and VEGFR2 lead to enhanced VEGFR2 and to reduced VEGFR1 signalling. A possible inhibitor is bevacizumab targeting VEGF. Grey, circled with light red: decreased signalling.
Figure 3. RAS/MAPK/ERK and PI3K/AKT/mTOR signalling involved in vascular tumours and vascular malformations. (a) Mutations in GNAQ/11, RASA1, EPHB4, TIE2, MAP3K3, KRIT1, malcavernin, PDCD10, RAS, BRAF and MAP2K1 lead to the activation of RAS/MAPK/ERK signalling. Inhibitors Vemurafenib and Trametinib target BRAF and MEK, respectively. (b) Mutations in TIE2, PIK3CA, PTEN, ALK1, BMP9/10 and endoglin activate PI3K/AKT/mTOR signalling. Inhibitor rapamycin targets mTOR. ALK1, BMP9/10, endoglin and SMAD4 downregulate BMP9/10 signalling, leading to an enhanced vessel formation. Thalidomide could be utilised. Red: gain‐of‐function; light red: loss‐of‐function; black, circled with red: enhanced signalling; grey, circled with light red: decreased signalling; EC: endothelial cell.
Figure 4. HGF and TGF‐ß signalling in GVM. Mutations in glomulin may lead to enhanced PI3K signalling as well as to a downregulated TGF‐ß/Smad signalling. Light red: loss‐of‐function; black, circled with red: enhanced signalling; grey, circled with light red: decreased signalling; vSMC: vascular smooth muscle cell.
Figure 5. VEGFR3 signalling involved in different types of lymphedemas. Mutations in VEGFR3, ADAMTS3, CCBE1, IKBKG, SOX18 and FOXC2 lead to changes in signalling in LECs. Mutations in Cx47 may lead to changes in gap junctions and to disruption of lymphatic flow. Red: gain‐of‐function; light red: loss‐of‐function; grey, circled with light red: decreased signalling; LEC: lymphatic endothelial cell.


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Further Reading

Boon LM and Vikkula M (2012) Vascular malformations. In: Fitzpatrick TB (ed) Dermatology in General Medicine, 8th, Chapter 172 edn, pp. 2076–2094. New York: McGraw‐Hill Professional Publishing.

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Nguyen HL, Boon LM and Vikkula M (2017) Vascular anomalies caused by abnormal signaling within endothelial cells: targets for novel therapies. Seminars in Interventional Radiology 34 (3): 233–238.

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Queisser, Angela, Boon, Laurence M, and Vikkula, Miikka(Mar 2018) Molecular Genetics of Vascular Malformations. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021459.pub2]