Neurofibromatosis 2 alleviates ferroptosis and fibrosis in the aortas of spontaneously hypertensive rats through the Yes-associated protein pathway.

Abstract

Neurofibromatosis 2 (NF2) is a tumor suppressor gene that plays a pivotal role in regulating cell growth and survival. There was evidence that patients with NF2 gene mutations have higher blood pressure. However, the specific role of NF2 in vascular remodeling caused by hypertension remains poorly understood. In this study, we found that NF2 expression was decreased in the aortas of spontaneously hypertensive rats (SHRs), and identified it as a critical regulator in vascular smooth muscle cells (VSMCs). Overexpression of NF2 in SHRs led to a reduction in blood pressure, alleviated vascular remodeling and mitigated aortic ferroptosis and fibrosis. Mechanistic investigations revealed that NF2 exerted its effects by modulating Yes-associated protein (YAP), preventing its nuclear translocation. Notably, the beneficial effects of NF2 overexpression were reversed by the administration of YAP agonist (PY60). Similar results were obtained in vitro. Our findings highlight the critical role of NF2 in regulating vascular remodeling and provide new insights for potential therapeutic strategies targeting NF2 and YAP in hypertension-related vascular complications.