Disorganized vascular structures in sporadic venous malformations: a possible correlation with balancing effect between Tie2 and TGF-β

Abstract

Venous malformations (VMs) are among the most common slow-flow vascular malformations characterized by irregular venous channels, luminal thrombi, and phleboliths. To systematically manifest the disorganized vascular structures in sporadic VMs, we initially evaluated histopathological characteristics, perivascular cell coverage, adhesion molecules expression and vascular ultrastructures. Then, the expression of Tie2 and TGF-β in VMs was detected. Meanwhile, the in vitro studies were performed for mechanism investigation. Our data showed that the perivascular α-SMA+ cell coverage and expression of adhesion molecules in VMs were significantly decreased compared with those in the normal skin tissues. We also found that the expression and phosphorylation levels of Tie2 were upregulated, whereas TGF-β was downregulated in VMs, and they were negatively correlated. Moreover, the in vitro results also revealed a possible balancing effect between Tie2 and TGF-β, as demonstrated by the findings that Ang-1 (agonist of Tie2) treatment significantly downregulated TGF-β expression, and treatment with recombinant TGF-β could also suppress Tie2 expression and phosphorylation. This study provided strong evidence supporting the disorganized vascular structures and dysregulation of related molecules in sporadic VMs, and demonstrated a possible balancing effect between Tie2 and TGF-β, which might help to develop novel therapeutics for vascular disorganization-related disorders.

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.…”

“…2,21 In contrast, VM are histologically characterized by disorganized vascular structures containing dilated vascular channels with reduced SMC coverage. 10,22 Reasonably, the characteristic paucity of surrounding vascular SMC is used as a hallmark of vascular destabilization. 10,12,23 Of note, accumulating evidence suggests that perivascular ECM, a crucial modulator of cell behavior and vascular morphogenesis, is capable of regulating proliferation, migration and differentiation of SMC.…”

“…10,22 Reasonably, the characteristic paucity of surrounding vascular SMC is used as a hallmark of vascular destabilization. 10,12,23 Of note, accumulating evidence suggests that perivascular ECM, a crucial modulator of cell behavior and vascular morphogenesis, is capable of regulating proliferation, migration and differentiation of SMC. [24][25][26] Meanwhile, alterations of ECM have been reported in VM previously.…”

“…In brief, 4-μm tissue sections were deparaffinized and analyzed as previously described. 10 Briefly, the tissue sections were dewaxed in xylene and then subject to rehydration in a graded series of ethanol and double-distilled water, followed by antigen retrieval at high pressure. Then, the sections were washed with phosphate-buffered saline (PBS), incubated in 3% hydrogen peroxide for 20 min at 37°C and blocked with goat serum for 20 min at 37°C.…”

“…Our previous studies have uncovered vascular destabilization as a fundamental pathological feature of VM. 10,12 Therefore, we next evaluated the relation of LOX expression to vascular destabilization in VM, which is marked by scarce smooth TGATCACAGGGTGCTGCTCA TGTGCAGTACATGCAAATCGC Fibronectin CGGTGGCTGTCAGTCAAAG AAACCTCGGCTTCCTCCATAA Collagen I GAGGGCCAAGACGAAGACATC CAGATCACGTCATCGCACAAC Collagen III GGAGCTGGCTACTTCTCGC GGGAACATCCTCCTTCAACAG Collagen IV GGACTACCTGGAACAAAAGGG GCCAAGTATCTCACCTGGATCA Elastin GCAGGAGTTAAGCCCAAGG TGTAGGGCAGTCCATAGCCA muscle cell coverage. As shown in Figure 2(a), skin samples exhibited dense distribution of perivascular α-SMA + cells and overexpression of LOX in vessels.…”