Vascular contribution to cognitive impairment in heart failure with preserved ejection fraction: TRPV4 and KLF2 as key mediators of neurovascular dysfunction in the ZSF1 model

Vascular cognitive impairment (VCI) shares major risk factors with heart failure with preserved ejection fraction (HFpEF), including obesity, diabetes and hypertension. Yet VCI research often relies on single-stimulus models, whereas patients experience combined risk factors. We therefore assessed cerebrovascular and cognitive phenotypes in an HFpEF model and investigated underlying mechanisms. Male Lean and Obese ZSF1 rats underwent longitudinal assessments of blood pressure, glucose, cardiac function, and behavioural performance. Cerebral blood flow and neurovascular coupling were assessed by laser speckle contrast imaging. White matter integrity, blood-brain barrier (BBB) permeability, and vascular density were analysed by (immuno)histochemistry. Cortical microvessels were isolated for transcriptomic profiling, and selected targets were validated using multiplex in-situ hybridization. Obese rats exhibited neurovascular uncoupling and impaired short- and long-term memory and spatial learning, accompanied by brain atrophy and reduced myelin. BBB permeability increased at 22-23 weeks and vascular density at 34-35 weeks in Obese vs Lean rats. Transcriptomic analysis of brain microvessels revealed altered processes related to angiogenesis, vasoreactivity, immune mechanisms and vascular remodelling, with consistent downregulation of Trpv4 and Klf2. Obese ZSF1 rats develop progressive neurovascular dysfunction associated with HFpEF onset and reduced Trpv4 and Klf2 expression in cerebral microvessels, two key vasoprotective genes.