Fast flow malformation microenvironment and its impact on growth behavior

Introduction Vascular malformations are associated with a congenital dysfunctional vessel development. Due to their flow characteristics they are distinguished in slow flow (SFM) and fast flow (FFM) malformations. They are regarded as rare diseases, which never regress. FFM grow proportionally with the child but can progress extensively later on in life. To date the cause of their expansive growth is unknown. Therefore, we evaluated the impact of the microenvironment on the proliferation of FFM.

Methods A PCR array analysis of angiogenesis-associated genes was performed with pooled patient samples of FFM and SFM (n=20). Immunohistochemical staining was performed to identify cytokines surrounding FFM (n=10) compared to SFM (n=10). Furthermore, neovascularization and endothelial cell (EC) proliferation was evaluated by immunohistochemistry. EC and fibroblasts were isolated from FFM and compared to human fibroblasts and microvascular EC in their response to cyclic mechanical stretching. Cytokine expression was quantified by ELISA and qPCR.

Results FFM show mRNA upregulation of TGFb, VEGF and VEGF-receptor NRP2 compared to SFM. The microenvironment of FFM demonstrates higher expression of IL-17, TGFb, VEGF-receptor 2, enhanced proliferation in EC and higher neovascularization rates compared to SFM. In vitro cyclic mechanical stretching induces cellular proliferation and higher VEGF-expression in stretched FFM compared to non-stretched FFM. Stretched FFM show higher VEGF-expression than stretched human fibroblasts and microvascular EC.

Conclusions Mechanical stress causes increased cellular proliferation of FFM through activation of VEGF-signaling. High VEGF-levels interacting with angiogenesis-promoting cytokines, like IL-17 and TGFb, induce the growth of FFM.

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Publication History

Article published online:
13 May 2021