Sphingosine-1-Phosphate–Dependent Activation of p38 MAPK Maintains Elevated Peripheral Resistance in Heart Failure Through Increased Myogenic Vasoconstriction

Abstract

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...

Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes

“…This heterogeneity explains why global cerebral blood flow and systemic hemodynamic parameters do not change at this time point in our model: in the brain, the microvascular effects are localized and likely compensated by collateral blood supply; systemically, skeletal muscle resistance arteries, the prominent regulators of total peripheral resistance, have not been recruited into an augmented myogenic phenotype. In principle, all four artery types are capable of increasing myogenic tone in pathological settings (11,12,16): augmenting myogenic responses in PCAs and skeletal muscle resistance arteries, therefore, may simply require more time or a more robust trigger (e.g., a higher glucose elevation). Indeed, even the enhancement of mesenteric and olfactory artery myogenic tone is far from rapid (i.e., requires .4 weeks): it is tempting to speculate, therefore, that hypertension (28) and cerebral perfusion deficits (27) emerge at later time points, as vascular beds are progressively recruited into an augmented myogenic tone phenotype.…”

“…*P < 0.05 for an unpaired comparison. myogenic tone in these arteries (10)(11)(12)16). HFD/STZ augments mesenteric and olfactory cerebral artery myogenic tone without altering PE responsiveness or passive diameter; myogenic tone in PCAs and cremaster skeletal muscle resistance arteries is not affected (Fig.…”

“…Mice were maintained on their respective diets for 12 additional weeks, at which point resistance arteries were isolated for assessment. Mesenteric (207 6 3 mm in diameter, n = 178), olfactory cerebral (113 6 2 mm, n = 140), cremaster skeletal muscle (79 6 2 mm, n = 15), and posterior cerebral arteries (PCAs) (147 6 3 mm, n = 28) were microsurgically isolated as previously described (10)(11)(12)16).…”

“…Resistance arteries were carefully cannulated onto micropipettes, pressurized, and warmed to 37°C in MOPS-buffered saline as previously described (10)(11)(12)16). Mouse olfactory and PCAs were pressurized to 45 mmHg; mouse mesenteric and human skeletal muscle resistance arteries were pressurized to 60 mmHg; and all treatments were diluted in MOPS-buffered saline.…”

Sphingosine-1-Phosphate as a Potential Target for the Treatment of Myocardial Infarction

“…In addition, mice lacking S1P2 receptors or SPKs did not show enhanced myogenic responses after MI. 69 In addition to these data implicating S1P2 receptors and SPKs, the cystic fibrosis transmembrane conductance regulator (which is thought to decrease extracellular S1P by transporting it into the cells, where it is degraded 71 ) may also modulate microvascular S1P signaling in heart failure. This transporter is downregulated in vitro and in vivo by TNFα, and in heart failure, suggesting that it is a fundamental mechanism with implications for systemic S1P effects.…”