FXR deletion amplifies stress-driven vascular patterning defects in the OIR model of ROP

Retinal vasculature development relies on precisely coordinated interactions between migrating endothelial cells and the underlying astrocyte scaffold. Disruption of this process is a hallmark of retinopathy of prematurity (ROP). The bile-acid-activated nuclear receptor, the Farnesoid X receptor (FXR), has been implicated in vascular and inflammatory regulation, yet its role in retinal angiogenesis remains largely unexplored. Using the oxygen-induced retinopathy (OIR) model, we examined how loss of FXR signaling influences retinal vascular patterning and pathological angiogenesis across the major stages of disease progression: hyperoxia (P7-P10), hypoxia-driven neovascularization (P12-P17), physiological revascularization (P17-P23), and long-term structural and functional recovery (P45). During early postnatal development, FXR deletion (FXR-/-) disrupted endothelial migration along the astrocytic template. At P10, FXR-/- retinas exposed to hyperoxia displayed markedly increased vaso-obliteration compared with wild-type controls, accompanied by sparse vascular meshwork, reduced astrocyte density, and pronounced gliosis indicative of impaired astrocyte-mediated vascular patterning in both superficial and deep plexuses. By P17, FXR deficiency further exacerbated disease severity, with enlarged central avascular zones and increased neovascular tuft formation, reflecting heightened sensitivity to hypoxia-induced, VEGF-driven angiogenesis. Further, FXR loss impaired this essential repair phase (P17-P23), resulting in delayed revascularization, decreased vascular density, and abnormal vessel architecture. Additionally, long-term evaluations at P45 aligned with this pattern, revealing persistent vascular dilation, arterial tortuosity, retinal thinning, and reduced ERG amplitudes in OIR-exposed retinas, even after neovascular regression. Together, these findings identify FXR as a key regulator of retinal vascular survival, angiogenic signaling, and post-injury remodeling. FXR deficiency intensifies vascular injury during hyperoxia, exacerbates pathological neovascularization during hypoxia, and impairs revascularization and long-term visual recovery. This data highlights FXR signaling as a promising therapeutic target for enhancing vascular repair and mitigating chronic neurovascular dysfunction in ROP. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.