Angiotensin II-induced hypertension does not exacerbate α-SYNUCLEIN pathology in a mouse model of Parkinson's disease.

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Parkinson's disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic neurons accompanied by chronic neuroinflammation and α-SYNUCLEIN (α-SYN) aggregation. Increasing evidence suggests that cardiovascular comorbidities, including arterial hypertension, may contribute to neurodegenerative processes through vascular dysfunction and sustained inflammatory signaling. However, whether hypertension directly exacerbates α-SYN-induced neurodegeneration and inflammasome activation remains unclear. Here, we investigated the impact of chronic Angiotensin II (AngII)-induced hypertension in an adeno-associated viral vector (AAV)-based mouse model of PD driven by unilateral overexpression of human α-SYN in the Substantia Nigra (SN). Chronic AngII infusion produced a robust hypertensive phenotype but did not aggravate α-SYN-induced loss of tyrosine hydroxylase-positive dopaminergic neurons. Similarly, hypertension failed to modify α-SYN-driven astrogliosis, microgliosis, or microglial morphological activation. Molecular analyses revealed that α-SYN overexpression markedly increased the expression of inflammatory mediators and pyroptosis-related genes, including Nlrp3, Asc, Casp1, Il1b, Il18rap, and Gsdmd. Nevertheless, hypertension did not potentiate these responses. Immunofluorescence analyses further demonstrated that GSDMD expression was predominantly localized in IBA1-positive microglial cells and was significantly elevated following α-SYN overexpression independently of hypertensive status. Collectively, these findings indicate that chronic AngII-induced hypertension is insufficient to exacerbate early α-SYN-mediated neurodegeneration, gliosis, or inflammasome-associated pyroptotic pathways in the SN. Our study suggests that α-SYN pathology itself constitutes the dominant driver of neuroinflammatory activation in this experimental paradigm and that additional vascular or aging-related mechanisms may be required for hypertension to significantly influence PD progression.

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