Retinal Angiogenesis in Methamphetamine Self-Administration Rats.

Purpose: Given the evidence of a link between methamphetamine (METH) exposure and retinal vascular abnormalities, this study aims to investigate the molecular and cellular mechanisms underlying METH-induced retinal angiogenesis using a unique self-administration rat model and primary rat retinal microvascular endothelial cells (RRMECs).

Method: To model the impact of compulsive use of METH, rats underwent an 8-week METH long-access self-administration protocol, with retinal tissues analyzed using whole retinal flatmount imaging and vascular network quantification. Proteomic analysis via liquid chromatography/tandem mass spectrometry identified differentially expressed proteins, while RRMECs were treated with METH to assess molecular changes through immunoblotting and quantitative RT-PCR.

Results: Consistent with compulsive use of METH in humans and our previous experience with this model, rats self-administered high levels of METH. METH self-administration elevated dopamine levels in the vitreous humor and increased vascular density in both superficial and deep capillary layers across central, mid-peripheral, and peripheral retina regions. Proteomic analysis revealed 148 differentially expressed retinal proteins, with gene ontology enrichment highlighting pathways related to abiotic stimuli, hypoxia, and ischemia. Increased hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor a (VEGFa) expression confirmed a hypoxia-driven angiogenesis process, further supported by in vitro experiments showing enhanced endothelial cell proliferation and HIF-1α/VEGFa expression. Additionally, TAAR-1 upregulation in both the retina and endothelial cells was observed, with TAAR-1 antagonism reducing METH-induced endothelial cell proliferation and modulating HIF-1α/VEGFa signaling.

Conclusions: METH self-administration leads to significant retinal vascular changes and angiogenesis, driven by upregulation of hypoxia-related pathways. TAAR-1 plays a critical role in endothelial cell proliferation through the HIF-1α/VEGFa pathway, potentially contributing to pathological retinal conditions.