Constitutive smooth muscle tumour necrosis factor regulates microvascular myogenic responsiveness and systemic blood pressure

Jeffrey T. Kroetsch, Andrew S. Levy, Hangjun Zhang, Roozbeh Aschar-Sobbi, Darcy Lidington, Stefan Offermanns, Sergei A. Nedospasov, Peter H. Backx, Scott P. Heximer and Steffen-Sebastian Bolz ()
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Jeffrey T. Kroetsch: Faculty of Medicine, University of Toronto, 1 King’s College Circle, Medical Sciences Building
Andrew S. Levy: Faculty of Medicine, University of Toronto, 1 King’s College Circle, Medical Sciences Building
Hangjun Zhang: Faculty of Medicine, University of Toronto, 1 King’s College Circle, Medical Sciences Building
Roozbeh Aschar-Sobbi: University Health Network, R. Fraser Elliott Building
Darcy Lidington: Faculty of Medicine, University of Toronto, 1 King’s College Circle, Medical Sciences Building
Stefan Offermanns: Max-Planck-Institute for Heart and Lung Research
Sergei A. Nedospasov: Engelhardt Institute of Molecular Biology and Lemonosov Moscow State University
Peter H. Backx: University Health Network, R. Fraser Elliott Building
Scott P. Heximer: Faculty of Medicine, University of Toronto, 1 King’s College Circle, Medical Sciences Building
Steffen-Sebastian Bolz: Faculty of Medicine, University of Toronto, 1 King’s College Circle, Medical Sciences Building

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Tumour necrosis factor (TNF) is a ubiquitously expressed cytokine with functions beyond the immune system. In several diseases, the induction of TNF expression in resistance artery smooth muscle cells enhances microvascular myogenic vasoconstriction and perturbs blood flow. This pathological role prompted our hypothesis that constitutively expressed TNF regulates myogenic signalling and systemic haemodynamics under non-pathological settings. Here we show that acutely deleting the TNF gene in smooth muscle cells or pharmacologically scavenging TNF with etanercept (ETN) reduces blood pressure and resistance artery myogenic responsiveness; the latter effect is conserved across five species, including humans. Changes in transmural pressure are transduced into intracellular signals by membrane-bound TNF (mTNF) that connect to a canonical myogenic signalling pathway. Our data positions mTNF ‘reverse signalling’ as an integral element of a microvascular mechanosensor; pathologic or therapeutic perturbations of TNF signalling, therefore, necessarily affect microvascular tone and systemic haemodynamics.

Date: 2017
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DOI: 10.1038/ncomms14805

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