Plastic Surgery Research Council

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Venous Malformations are Proliferative: Clinical Implications
Michael Schonning, BS Biology, Ajit Muley, PhD, Carrie J. Shawber, PhD, June K. Wu, MD FACS.
Columbia University Medical Center, New York, NY, USA.

PURPOSE: Vascular Anomalies are divided into tumors and malformations. Vascular tumors are proliferative lesions, while vascular malformations are thought to be fully formed at birth and biologically quiescent. However, many venous malformations (VMs) progressively enlarge, affected patients experience worsening symptoms over time, and recurrence can occur after sclerotherapy and surgical resection, suggesting VMs are biologically active. We have isolated a CD133+ cell with progenitor and endothelial cell characteristics from VMs that we termed venous malformation endothelial cells (VMECs). VMECs were able to recapitulate VMs in a murine model, suggesting that they are the cell of origin for these lesions. We hypothesize that VMs are hyperplastic lesions arising from a proliferative pool of VMECs.

METHODS: Paraffin sections of VM specimens (n=4) were immunostained for Ki67, a marker of proliferation, and the endothelial cell (EC) marker, CD31. A proliferative index (Ki67+ ECs/total # ECs) was determined for VM specimens and control neonatal foreskin and adult skin. To determine individual EC length, vascular channel circumference (in μm) and number of DAPI+ ECs were determined. VMECs were isolated from VM specimens and ERK activation determined relative to normal endothelial cells (HMVECs) isolated from neonatal foreskin. Western blotting for total ERK (ERK) and phospo-ERK (pERK) was performed and pERK/ERK ratio determined (n=2). VMECs were stained with antibodies against ERK and pERK (n=3).

RESULTS: When compared to controls neonatal foreskin and adult skin, VMs had a significant increase in Ki67+ ECs (p<0.0001; Figure 1). Individual EC length was not different between vessels in VM tissues and control tissues (Figure 1). Finally, CD133+ VMECs had increased ERK activation when compared to HMVECs by Western blot and immunofluorescent staining (Figure 2).

CONCLUSIONS: VM vessels had an increase in EC proliferation and not EC length, suggesting the dilated vessels in VMs arise due to EC hyperproliferation and not EC hypertrophy. As the ERK pathway promotes EC proliferation, the ERK activation in VMECs may promote the increase their proliferation. These results suggest that VMs are biologically active and proliferative lesions. A strategy of using an anti-proliferative medical therapy, in addition to sclerotherapy and surgical resection, may be efficacious in the treatment of VMs.


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