ERG Regulates Lymphatic Vessel Specification Genes and Its Deficiency Impairs Wound Healing‐Associated Lymphangiogenesis

Abstract

ObjectiveRarefaction of blood and lymphatic vessels in the skin has been reported in SSc (systemic sclerosis, scleroderma). ERG and FLI1 are important regulators of angiogenesis, but their role in lymphatic vasculature is less known. The goal of this study was to determine the role of ERG and FLI1 in postnatal lymphangiogenesis and SSc lymphatic system defects.MethodsImmunofluorescence was used to detect ERG and FLI1 in SSc and healthy control (HC) skin biopsies. Transcriptional analysis of ERG or FLI1 silenced human dermal lymphatic endothelial cells (LECs) was performed using microarrays. Effects of ERG/FLI1 deficiency on in vitro tubulogenesis in human dermal LECs was examined using a Matrigel assay. Erg and Fli1 endothelial specific knockouts and Erg lymphatic specific knockouts were generated to examine vessel regeneration in mice.ResultsERG and FLI1 protein levels were reduced in the blood and lymphatic vasculature in SSc skin biopsies. ERG was shown to regulate genes involved in lymphatic vessel specification, including VEGFR3/FLT4, LYVE‐1, SOX18, and PROX1, while FLI1 enhanced the function of ERG. ERG/FLT4 pathway regulated in vitro tubulogenesis in human LECs. Deficiency of Erg or Fli1 similarly impaired the function of blood vessels in mice. However, only Erg deficiency affected the regeneration of lymphatic vessels during wound healing.ConclusionERG and FLI1 are essential regulators of blood and lymphatic vessel regeneration. Deficiency of ERG and FLI1 in SSc endothelial cells, may contribute to impairment of blood and lymphatic vasculature in SSc patientsimage