A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Henna Ilmonen
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Pia Vuola
Department of Plastic Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland; VASCERN VASCA European Reference Centre, Helsinki University Hospital, Helsinki, Finland
Heta Rasinkangas
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Heidi H Pulkkinen
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Sara Keränen
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Kimmo Lappalainen
VASCERN VASCA European Reference Centre, Helsinki University Hospital, Helsinki, Finland; Department of Radiology, HUS Diagnostic Center and Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Jouko Lohi
VASCERN VASCA European Reference Centre, Helsinki University Hospital, Helsinki, Finland; Department of Pathology, HUSLAB, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Johanna Aronniemi
VASCERN VASCA European Reference Centre, Helsinki University Hospital, Helsinki, Finland; Department of Radiology, HUS Diagnostic Center and Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Tiit Örd
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
Päivi Salminen
VASCERN VASCA European Reference Centre, Helsinki University Hospital, Helsinki, Finland; Department of Pediatric Surgery, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
Erkki Tukiainen
Department of Plastic Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland; Science Service Center, Kuopio University Hospital, Kuopio, Finland; Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland
Background: Sporadic venous malformation (VM) and angiomatosis of soft tissue (AST) are benign, congenital vascular anomalies affecting venous vasculature. Depending on the size and location of the lesion, symptoms vary from motility disturbances to pain and disfigurement. Due to the high recurrence of the lesions, more effective therapies are needed. Methods: As targeting stromal cells has been an emerging concept in anti-angiogenic therapies, here, by using VM/AST patient samples, RNA-sequencing, cell culture techniques, and a xenograft mouse model, we investigated the crosstalk of endothelial cells (EC) and fibroblasts and its effect on vascular lesion growth. Results: We report, for the first time, the expression and secretion of transforming growth factor A (TGFA) in ECs or intervascular stromal cells in AST and VM lesions. TGFA induced secretion of vascular endothelial growth factor (VEGF-A) in paracrine fashion, and regulated EC proliferation. Oncogenic PIK3CA variant in p.H1047R, a common somatic mutation found in these lesions, increased TGFA expression, enrichment of hallmark hypoxia, and in a mouse xenograft model, lesion size, and vascularization. Treatment with afatinib, a pan-ErbB tyrosine-kinase inhibitor, decreased vascularization and lesion size in a mouse xenograft model with ECs expressing oncogenic PIK3CA p.H1047R variant and fibroblasts. Conclusions: Based on the data, we suggest that targeting of both intervascular stromal cells and ECs is a potential treatment strategy for vascular lesions having a fibrous component. Funding: Academy of Finland, Ella and Georg Ehnrooth foundation, the ERC grants, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Jane and Aatos Erkko Foundation, GeneCellNano Flagship program, and Department of Musculoskeletal and Plastic Surgery, Helsinki University Hospital.
