Background-Sphingosine-1-phosphate (S1P) signaling is a central regulator of resistance artery tone. Therefore, S1P levels need to be tightly controlled through the delicate interplay of its generating enzyme sphingosine kinase 1 and its functional antagonist S1P phosphohydrolase-1. The intracellular localization of S1P phosphohydrolase-1 necessitates the import of extracellular S1P into the intracellular compartment before its degradation. The present investigation proposes that the cystic fibrosis transmembrane conductance regulator transports extracellular S1P and hence modulates microvascular S1P signaling in health and disease. Methods and Results-In cultured murine vascular smooth muscle cells in vitro and isolated murine mesenteric and posterior cerebral resistance arteries ex vivo, the cystic fibrosis transmembrane conductance regulator (1) is critical for S1P uptake; (2) modulates S1P-dependent responses; and (3) is downregulated in vitro and in vivo by tumor necrosis factor-␣, with significant functional consequences for S1P signaling and vascular tone. In heart failure, tumor necrosis factor-␣ downregulates the cystic fibrosis transmembrane conductance regulator across several organs, including the heart, lung, and brain, suggesting that it is a fundamental mechanism with implications for systemic S1P effects. Conclusions-We identify the cystic fibrosis transmembrane conductance regulator as a critical regulatory site for S1P signaling; its tumor necrosis factor-␣-dependent downregulation in heart failure underlies an enhancement in microvascular tone. This molecular mechanism potentially represents a novel and highly strategic therapeutic target for cardiovascular conditions involving inflammation. (Circulation. 2012;125:2739-2750.)Key Words: acute myocardial infarction Ⅲ hemodynamics Ⅲ myogenic vasoconstriction Ⅲ signal transduction Ⅲ vasomotor tone S phingosine-1-phosphate (S1P) is a ubiquitous signaling mediator that directs a diverse array of biological processes. 1 In the microcirculation, S1P is a potent vasoconstrictor and a central mediator regulating myogenic tone. [2][3][4][5] This confers S1P signaling with significant importance in the control of blood flow autoregulation, tissue perfusion, and systemic blood pressure. Editorial see p 2692 Clinical Perspective on p 2750The potent and pleiotropic effects of S1P are confined both spatially and temporally 6 ; however, the molecular mechanisms limiting S1P bioavailability are not completely understood. We have demonstrated that S1P phosphohydrolase-1 (SPP1), an intracellular enzyme primarily localized to the endoplasmic reticulum, 7,8 degrades extracellular S1P. 3 As a consequence, we concluded that an S1P "import" mechanism must be present in vascular smooth muscle cells. Boujaoude et al 9 have provided indirect evidence that the cystic fibrosis transmembrane conductance regulator (CFTR) could act as this S1P transporter and thereby limit S1P receptor-mediated effects. Accordingly, we have observed that CFTR inhibition specifically enhance...

Background-Heart failure is associated with neurological deficits, including cognitive dysfunction. However, the molecular mechanisms underlying reduced cerebral blood flow in the early stages of heart failure, particularly when blood pressure is minimally affected, are not known. Methods and Results-Using a myocardial infarction model in mice, we demonstrate a tumor necrosis factor-␣ (TNF␣)-dependent enhancement of posterior cerebral artery tone that reduces cerebral blood flow before any overt changes in brain structure and function. TNF␣ expression is increased in mouse posterior cerebral artery smooth muscle cells at 6 weeks after myocardial infarction. Coordinately, isolated posterior cerebral arteries display augmented myogenic tone, which can be fully reversed in vitro by the competitive TNF␣ antagonist etanercept. TNF␣ mediates its effect via a sphingosine-1-phosphate (S1P)-dependent mechanism, requiring sphingosine kinase 1 and the S1P 2 receptor. In vivo, sphingosine kinase 1 deletion prevents and etanercept (2-week treatment initiated 6 weeks after myocardial infarction) reverses the reduction of cerebral blood flow, without improving cardiac function. Conclusions-Cerebral artery vasoconstriction and decreased cerebral blood flow occur early in an animal model of heart failure; these perturbations are reversed by interrupting TNF␣/S1P signaling. This signaling pathway may represent a potential therapeutic target to improve cognitive function in heart failure.

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Key Words: myogenic response Ⅲ heart failure Ⅲ sphingosine-1-phosphate Ⅲ mitogen-activated protein kinase H eart failure (HF) is a progressive condition that affects more than 2% of the population and accounts for Ϸ$28 billion in health care costs in the United States. 1 The prevalence of HF is increasing worldwide, and given its adverse impacts on the quality and longevity of life, 1 the burdens imposed by HF are enormous. Irrespective of etiology, HF presents as a clinical syndrome of reduced cardiac output and or elevated cardiac filling pressures. [2][3][4] In the former, cardiac-renal-hormonal axes and sympathetic neural reflexes are activated in an attempt to maintain sufficient mean arterial pressure (MAP) for vital organ perfusion. 4 This is achieved through increased salt and water retention 4 (ultimately worsening the deleterious volume overload of HF), and through an increase in peripheral resistance (PR). 5 Although increased PR may support MAP in certain circumstances, chronic elevations in PR contribute to a pressure afterload that further limits cardiac output in HF, 3 and drives adverse cardiac remodeling. 3 Such "vicious cycles" are believed to play a key role in the progressive nature of HF, and many advances in its management have been aimed at Original received August 5, 2009; resubmission received June 18, 2010; revised resubmission received July 19, 2010; accepted July 20, 2010. In June 2010, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.5 days.From mitigating this pathophysiology. In general, increased PR in HF is thought to be conveyed by neurohumoral activation, including the sympathetic nervous system, 6 the renin-angiotensin system (RAS), 4 and local mechanisms such as the myogenic response. 7 Our present purpose was to investigate the molecular mechanisms that underlie the latter, ie, myogenic elevations of PR in HF, to identify potentially novel therapeutic targets. Indeed, growing evidence suggests that long-term elevations in PR depend more on "local" vascular mechanisms than systemic factors such as the sympathetic activation of orthostasis. 5 Moreover, reasons why chronic maintenance of high PR in HF by systemic sympathetic (ie, ␣ 1 -adrenergic) enhancement of peripheral vasoconstriction 2,8 is disadvantageous include: (1) increased sympathetic output compromises a failing myocardium (via tachycardia, arrhythmia, cytotoxicity 9 ); and (2) catecholamine potency diminishes because of adrenergic receptor desensitization. 10 -12 We thus posited that distinct local mechanisms would participate in chronic elevations in PR observed in HF. Supporting this premise, the maintenance of peripheral vascular tone largely depends on "myogenic" mechanisms intrinsic to vascular smooth muscle cells (VSMCs). 13 On a local level, myogenic mechanisms serve to adapt vascular tone to changes in transmural pressure. Systemically, myogenic vasoconstriction can amplify vasopressor responses by positive feedback on systemic blo...