Temporal Mapping of CSVD-Related White Matter Lesions and Concurrent Neurovascular Dysfunction in Spontaneously Hypertensive Rats.

OBJECTIVE: To define the critical onset window and mechanisms of white matter lesions (WMLs) in cerebral small vessel disease based on spontaneously hypertensive rat (SHR). METHODS: SHRs and age-matched Wistar-Kyoto (WKY) rats were assessed from 20 to 36 weeks of age. Systolic blood pressure, beam-walking performance, and magnetic resonance imaging (MRI)-based white matter changes were evaluated at 4-week intervals. At each time point, randomly selected animals were euthanized for histological analysis. Gait performance and novel object recognition were further assessed at 36 weeks of age. Additional histopathological, neurovascular, neuroinflammatory, transcriptomic, proteomic, and biochemical analyses were performed at the identified critical time point. RESULTS: SHRs developed sustained hypertension and early small-vessel morphological alterations from 20 weeks, followed by corpus callosum demyelination at 28 weeks and motor, gait, and non-spatial memory deficits by 36 weeks. MRI identified 28 weeks as the onset of detectable white matter microstructural impairment, marked by reduced fractional anisotropy, axial diffusivity, and increased radial diffusivity. At this stage, histological and molecular analyses confirmed myelin disruption, altered mature oligodendrocyte (OL)- and oligodendrocyte precursor cell (OPC)-associated marker profiles, microvascular rarefaction, blood-brain barrier disruption, and inflammation in SHRs. Transcriptomic analysis highlighted cAMP pathway dysregulation, whereas proteomic analysis identified Pde10a as a significantly upregulated candidate protein. Suppression of downstream cAMP/PKA/CREB signaling was further supported by biochemical validation. CONCLUSIONS: WMLs emerge at 28 weeks in SHRs and are accompanied by convergent neurovascular injury and inflammatory activation. Pde10a-associated cAMP signaling may represent a candidate mechanism associated with hypertension-related WML development in CSVD.