title: The TNF-α/sphingosine-1-phosphate signaling axis drives myogenic responsiveness in heart failure.
abstract: Heart failure (HF) is hallmarked by an increase in total peripheral resistance (TPR) that compensates for the drop in cardiac output. While initially allowing for the maintenance of mean arterial pressure at acceptable levels, the long-term upregulation of TPR is prone to compromise cardiac performance and tissue perfusion, and to ultimately accelerate disease progression. Augmented vasoconstriction of terminal arteries, the site of TPR regulation, is cooperatively driven by mechanisms such as: (i) endothelial dysfunction, (ii) increased sympathetic activity and (iii) enhanced pressure-induced myogenic responsiveness. Herein, we review emerging evidence that the increase in myogenic responsiveness is central to the long-term elevation of TPR in HF. On a molecular level, this augmented intrinsic response is governed by an activation of the tumor necrosis factor-α (TNF-α)/sphingosine-1-phosphate signaling axis in microvascular smooth muscle cells. The beneficial effect of TNF-α scavenging strategies on tissue perfusion in HF mouse models adds to the gaining momentum to revisit the use of anti-TNF-α treatment modalities in discrete HF patient populations.
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ont., Canada. jeff.kroetsch@utoronto.ca
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kroetsch
authors.forename: Steffen-Sebastian
authors.initials: SS
authors.lastname: Bolz
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D002302:Cardiac Output / Q000502:physiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology; D004730:Endothelium, Vascular / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology*; D006801:Humans; D008246:Lysophospholipids / Q000502:physiology*; D024510:Muscle Development / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D014655:Vascular Resistance / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology
chemical_list: D008246:Lysophospholipids; D014409:Tumor Necrosis Factor-alpha; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C060506:sphingosine 1-phosphate; D013110:Sphingosine