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

Abstract

Background The development of vascular cognitive impairment (VCI) and heart failure with preserved ejection fraction (HFpEF) are strongly associated with comorbidities such as obesity, diabetes, hypertension, and aging. Microvascular dysfunction may be key a pathological step in the development of cognitive dysfunction during HFpEF. Hence, we aimed to evaluate the cerebrovascular and cognitive phenotype in ZSF1 rats and identify molecular processes central to the development of VCI during HFpEF. Methods Male Lean and Obese rats underwent blood pressure and glucose measurements, echocardiography and a series of behavioural tasks at three different time points. Cerebral blood flow was measured over the barrel cortex using laser speckle contrast imaging and neurovascular coupling was assessed upon whisker stimulation. Brain immunohistochemistry was performed to assess blood-brain barrier (BBB) integrity and vascular density. Lastly, isolated cortical microvessels were used for transcriptomic analysis, and selected targets were validated in brain sections via fluorescent multiplex in-situ hybridization. Results Obese ZSF1 rats exhibited neurovascular uncoupling, along with an impaired short- and long-term memory, as well as spatial learning. In addition, BBB permeability and cerebral vascular density were elevated in Obese vs Lean at 22-23 and 34-35 weeks of age, respectively. Transcriptomic analysis of brain microvessels revealed the regulation of processes related to angiogenesis, vasoreactivity, immune mechanisms and vascular remodelling. Among the top regulated biological processes, Trpv4 and Klf2 were found to be consistently downregulated in Obese vs Lean rats and involved in many of the top regulated biological processes. This was further verified in brain sections at 22-23 weeks of age. Conclusion Obese ZSF1 rats develop cognitive impairment, which is related to dysfunction of the neurovascular unit. This cerebrovascular phenotype progresses along with the onset of HFpEF and is associated with downregulation of Trpv4 and Klf2 in cerebral microvessels, two key genes known for their vasoprotective actions.

Competing Interest Statement

The authors have declared no competing interest.