Ningning Chen, Xiaohang Yin, Dong Wang, Dongmei Zhou, Lili Kang, Xiaoying Li
Children’s Hospital Affiliated to Shandong University (Jinan Children’s Hospital), Cheeloo College of Medicine and Shandong University.
China
Biochemical Pharmacology
Biochem Pharmacol 2025;
DOI: 10.1016/j.bcp.2025.117572
Abstract
Persistent pulmonary hypertension of the newborn (PPHN) is a severe and progressive disorder with limited therapeutic options. Dysfunction of pulmonary artery endothelial cells (PAECs) underpin the pathogenesis and progression of PPHN, but the precise mechanisms remain poorly defined. Endothelial Kruppel-like factor 2 (KLF2) is a key transcription factor required for vascular homeostasis. Here, we investigated the role of KLF2 in PAEC function in PPHN. We found reduced expression of KLF2 in infants with PPHN. Silencing of KLF2 in PAECs led to dysregulated secretion of vasoactive mediators, characterized by diminished endothelial nitric oxide synthase (eNOS) and enhanced endothelin-1 (ET-1) expression. Moreover, KLF2-deficient PAECs exhibited enhanced proliferative and migratory capacities, whereas KLF2 overexpression produced opposite effects. Mechanistically, we found that loss of KLF2 upregulated matrix metalloproteinase-1 (MMP-1) expression by facilitating the recruitment of the acetyltransferase p300 and RNA polymerase II to the MMP-1 promoter, thereby driving PAEC proliferation and migration. Importantly, pharmacological activation of KLF2 with calycosin mitigated hypoxia-induced endothelial dysfunction and attenuated pulmonary vascular remodeling in a neonatal rat model. In conclusion, our findings demonstrate that KLF2 deficiency impairs PAEC function and exacerbates pulmonary vascular remodeling in PPHN. These results highlight KLF2 activation as a promising therapeutic strategy for the treatment of PPHN in preclinical models.
Category
Class I. Persistent Pulmonary Hypertension of the Newborn
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Genetic Factors Associated with Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
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