Development of Molecular Therapies for Venous Malformations

Abstract

Vascular anomalies are localized defects of morphogenesis that can affect lymphatic and blood vessels. They are generally called birthmarks, typically observed soon after birth and occurring in up to 10% of children. Based on their clinical and histological characteristics, they are classified into vascular tumours and vascular malformations. The most common malformations are venous malformations (VMs) resulting in chronic vascular diseases that can be associated with significant morbidity necessitating often demanding and repeating clinical management. The current treatment is based on surgical resection and sclerotherapy, which can be impossible due to the size or location of lesions or ineffective due to the regrowth of malformed vessels. Therefore, medical therapies for VMs are highly desired. Recent studies have identified genetic defects that result in the constantly active endothelial cell receptor tyrosine kinase TIE2/phosphoinositide 3-kinase PI3K signalling pathway as a frequent cause for VMs. The first treatment to inhibit this pathway with sirolimus indicated that molecular treatment can be effective against VMs. In addition, certain VM 'hotspot' mutations have been previously found in tumours, providing the rationale for the exploration and repurposing of existing and investigational cancer drugs for VMs. Finally, discoveries of molecular and cellular abnormalities that characterize a large proportion of VMs and the generation of pre-clinical VM mouse models provide the necessary basis for the development of the targeted molecular treatment strategies we discuss in this MiniReview.

Angiopoietin-4-dependent venous maturation and fluid drainage in the peripheral retina

“…On the other hand, in addition to ligand-specific effects, our in vitro characterization also revealed redundant functions between angiopoietins 1 and 4, suggesting that differential, spatiotemporally regulated expression provides an important mechanism for complementary and sequential roles of angiopoietins to establish retinal circulation system. Moreover, based on reported venous-specific effects of inducible Tie2 deletion in retina ( Chu et al, 2016 ) and over-activating TIE2 mutations in venous malformations ( Kangas et al, 2018 ), Tie2 signaling appears particularly important to venous development that may contribute to the vessel-type-specific phenotype in Angpt4 -/- mice.…”

Downregulation of lysyl oxidase in venous malformations: Association with vascular destabilization and sclerotherapy

“…8,9 Pathologically, VM are composed of disorganized vessels with a thin EC lining, covered by rare, unevenly distributed SMC and poorly organized ECM. 10,11 Previous studies, including ours, have shown that markedly decreased SMC coverage is a prominent hallmark of vascular destabilization in VM, which is associated with dysregulation of perivascular ECM. 10,12 Extracellular matrix regulation involves a dynamic process balanced by ECM deposition and degradation, which is orchestrated by a variety of signal molecules and enzymes.…”

“…[24][25][26] Meanwhile, alterations of ECM have been reported in VM previously. 11,27 However, the regulation of perivascular ECM and its potential roles in VM remain largely unclear.…”

Celecoxib as a Potential Treatment for Intractable Lymphatic Malformation

“…9 Therefore, new treatment modalities for LM are being sought. 10 Until now, the most promising drug has been sirolimus. Sirolimus inhibits TIE2-vascular malformation (VM)-and PIK3CA-VM-induced Akt activation, which is a major molecular abnormality associated with VM.…”