Downregulation of Trpv4 and Klf2 in brain microvessels is associated with the progression of neurovascular dysfunction and cognitive impairment in a model of heart failure with preserved ejection fraction
Abstract
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.
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BibTeX
@article{lambrichts2026downregulation,
title = {{Downregulation of Trpv4 and Klf2 in brain microvessels is associated with the progression of neurovascular dysfunction and cognitive impairment in a model of heart failure with preserved ejection fraction}},
author = {Sara Mp Lambrichts and Laura van der Taelen and Irene Pastor and Peter Leenders and Nicole Bitsch and Daria Majcher and Denise Hermes and Steven Simmonds and Marcel van Herwijnen and Rick Kamps and Ellen Weltjens and Phyllis Jj Jessen and Hellen Steinbusch and Floor Arentz and Maximilian Wiesmann and Amanda Kiliaan and Florian Caiment and Martina Kutmon and Elizabeth Av Jones and Robert van Oostenbrugge and Sébastien Foulquier},
journal = {Journal of Cerebral Blood Flow and Metabolism},
year = {2026},
month = jun,
doi = {10.1177/0271678x261462714},
url = {https://hal.science/hal-05787321v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Downregulation of Trpv4 and Klf2 in brain microvessels is associated with the progression of neurovascular dysfunction and cognitive impairment in a model of heart failure with preserved ejection fraction
AU - Sara Mp Lambrichts
AU - Laura van der Taelen
AU - Irene Pastor
AU - Peter Leenders
AU - Nicole Bitsch
AU - Daria Majcher
AU - Denise Hermes
AU - Steven Simmonds
AU - Marcel van Herwijnen
AU - Rick Kamps
AU - Ellen Weltjens
AU - Phyllis Jj Jessen
AU - Hellen Steinbusch
AU - Floor Arentz
AU - Maximilian Wiesmann
AU - Amanda Kiliaan
AU - Florian Caiment
AU - Martina Kutmon
AU - Elizabeth Av Jones
AU - Robert van Oostenbrugge
AU - Sébastien Foulquier
PY - 2026
DA - 2026/06/12
JO - Journal of Cerebral Blood Flow and Metabolism
DO - 10.1177/0271678x261462714
UR - https://hal.science/hal-05787321v1
AB - 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.
SN - 0271-678X
SN - 1559-7016
ER -