Elevated TGF-β1 impairs synaptic and cognitive function through activation of Smad2/3-Sp1 pathway in AngII-related hypertension

Vascular dementia (VaD) is characterized by cognitive decline due to reduced cerebral blood flow, although its molecular mechanisms remain unclear. This study shows that angiotensin II (AngII) elevates blood pressure, reduces hippocampal blood flow, and impairs synaptic and cognitive function, which correlates with increased TGF-β1 levels. Overexpressing TGF-β1 in rats induces similar deficits, while its downregulation partially mitigates these effects, with the exception of hypoperfusion. Phosphorylation of Smad2/3, downstream of TGF-β1, is elevated in AngII-treated rats and TGF-β1-exposed neurons, and inhibiting Smad2/3 activation prevents synaptic damage. Additionally, phosphorylated Smad2/3 interacts more with the transcription factor Sp1 in hippocampal neurons of AngII-treated rats. Overexpression of Sp1 worsens synaptic and cognitive function, whereas Sp1 knockdown improves TGF-β1-induced impairments. These findings highlight TGF-β1 as a key mediator of AngII-induced cognitive deficits, beyond hypoperfusion, suggesting that targeting the TGF-β1/Smad2/3/Sp1 axis may offer therapeutic benefits for hypertension-related synaptic and cognitive dysfunction.