Microenvironmental Extracellular Matrix Remodeling Driven by GATA2 and GATA3 Deficiency Impairs Lymphatic Recanalization

Abstract

GATA2 is a transcription factor that is essential for vascular and lymphatic development. GATA2 deficiency causes lymphatic malformations and lymphedema. Delayed lymphatic recanalization after popliteal lymph node removal in Gata2 heterozygous (Gata2+/−) mice is associated with collagen accumulation in the surrounding tissue. In this study, we investigated whether extracellular matrix (ECM) alterations contribute to lymphatic recanalization by analyzing subcutaneous tissue from Gata2+/− and Gata2 and Gata3 double heterozygous (Gata2+/−::Gata3+/−) mice. RNA-seq analysis revealed changes in ECM-related and adhesion-associated genes in both genotypes. Histological analyses demonstrated collagen accumulation and disorganized collagen bundles in Gata2+/−::Gata3+/− mice. Immunostaining further revealed reduced elastin fibers and decreased numbers of fibroblasts in subcutaneous tissues of Gata2+/− and Gata2+/−::Gata3+/− mice. These findings suggest that abnormalities in ECM organization, including altered collagen and elastin structures and reduced fibroblast populations, may underlie collagen accumulation and impaired lymphatic recanalization. Notably, Gata2+/−::Gata3+/− mice exhibited a patchwork-like dermal phenotype reflecting features of both single mutants, possibly owing to mosaic transcriptional regulation within the GATA gene network. The microenvironmental ECM structure plays an important role in lymphatic recanalization following lymphatic injury.