Initiating Events of Retinopathy in Spontaneously Hypertensive Rats: Microvascular Rarefaction and Functional...

Target organ damage is crucial for hypertension risk stratification. However, the lack of sensitive assessment tools for early target organ damage in the presence of elevated blood pressure limits timely intervention. This study used the retina to investigate subclinical neurovascular damage and identify early imaging biomarkers.

We monitored male spontaneously hypertensive rats and Wistar-Kyoto controls weekly from 4 to 9 weeks of age. Weekly assessments included noninvasive blood pressure and multimodal fundus imaging, including optical coherence tomography, optical coherence tomography angiography and electroretinography. Histological analyses and fluorescein fundus angiography validated structural microvascular changes and blood-retinal barrier integrity.

The blood pressure of spontaneously hypertensive rats increased significantly from 5 weeks of age (P<0.05). At the prehypertensive stage (6 weeks), spontaneously hypertensive rats exhibited decreased superficial vascular plexus density and reduced scotopic electroretinography b-wave amplitude. Fluorescein fundus angiography demonstrated that the blood-retinal barrier remained functionally intact without leakage at this stage. These microvascular and functional deficits preceded structural changes on optical coherence tomography. Subsequently, vascular damage progressed to deeper plexuses, accompanied by inner retinal thinning, apoptosis, and continued functional decline. Linear mixed-effects modeling confirmed a negative correlation between the prehypertensive stage and decreased superficial vascular density (P<0.001).

In spontaneously hypertensive rats, superficial microvascular rarefaction and inner retinal dysfunction represent the initiating pathological events, preceding blood-retinal barrier breakdown and macrovascular remodeling. Optical coherence tomography angiography-quantified superficial vascular plexus density is a sensitive and objective imaging biomarker for assessing retinal damage during the prehypertensive stage, which significantly precedes macrovascular signs.