AUTHOR=Liu Lu , Wang Linmei , Luo Jiaxin , Yu Jiayun , Xie Liang , Liu Yang , Xu Hong , Hu Fan , Liu Hanmin 

TITLE=Endothelial GNAQ p.R183Q mutation confers hemoporfin-mediated photodynamic therapy resistance and drives pathological angiogenesis via the angiopoietin-2/TIE2/PI3K/AKT pathway

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 13 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2025.1622961

DOI=10.3389/fcell.2025.1622961

ISSN=2296-634X

ABSTRACT=Hemoporfin-mediated photodynamic therapy (HMME-PDT) has demonstrated significant advantages in the treatment of Port-wine stains (PWSs). However, the therapeutic efficacy of HMME-PDT remains suboptimal in a subset of patients. Somatic mosaic mutations in GNAQ (c.548G>A, p. R183Q) are frequently detected in endothelial cells (ECs) of lesions and represent a common pathogenic mechanism. In this study, we successfully established an in vitro model of PWSs by introducing the GNAQ p. R183Q mutation into HUVECs using lentiviral infection. Our results revealed that GNAQ p. R183Q mutation enhanced ECs proliferation, migration, and angiogenesis. Moreover, the mutation augmented anti-apoptotic mechanisms, thereby conferring heightened resistance to HMME-PDT-induced apoptosis. Residual angiogenic activity persisted following HMME-PDT treatment. These effects are likely mediated by activation of the angiopoietin-2 (ANGPT2)/TIE2/PI3K/AKT signaling axis. Knockdown of ANGPT2 partly reversed these phenotypic alterations and significantly enhanced the efficacy of HMME-PDT. The combination of HMME-PDT with anti-ANGPT2 therapy holds promise for enhancing therapeutic efficacy, suppressing pathological angiogenesis, and ameliorating the clinical manifestations of PWSs.