Endothelial GNAQ p.R183Q Mutation Confers Hemoporfin-Mediated Photodynamic Therapy Resistance and Drives Pathological Angiogenesis via the Angiopoietin-2/TIE2/PI3K/AKT Pathway

lu liu^1,2,3,4,5Linmei Wang^1,2,3,4,5Jiaxin Luo^1,2,3,4,5Jiayun Yu⁶Liang Xie^1,2,3,4,5Yang Liu^1,2,3,4,5Hong Xu^1,2,3,4,5Fan Hu^2,7*Hanmin Liu^1,2,3,4,5,8*

• ¹Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
• ²Key Laboratory of Birth Defect and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
• ³NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
• ⁴The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital，Sichuan University and School of Life Sciences of Fudan University, Chengdu, China
• ⁵Sichuan Birth Defects Clinical Research Center, West China Second University Hospital, Sichuan University, Chengdu, China
• ⁶Department of Radiotherapy, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, National Clinical Research Center for Geriatrics, Sichuan University, Chengdu, China
• ⁷Department of Pediatric Cardiology, West China Second University Hospital, Sichuan University, Chengdu, China
• ⁸Department of Pediatric Pulmonology and Immunology, WCSUH-Tianfu·Sichuan Provincial Children's Hospital, Sichuan University, Meishan, China

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.