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. Author manuscript; available in PMC: 2009 Feb 28.
Published in final edited form as: Auton Neurosci. 2008 Feb 29;138(1-2):9–23. doi: 10.1016/j.autneu.2007.11.001

Putative mechanisms behind effects of spinal cord stimulation on vascular diseases: a review of experimental studies

Mingyuan Wu 1, Bengt Linderoth 2, Robert D Foreman 1
PMCID: PMC2291393  NIHMSID: NIHMS39626  PMID: 18083639

Abstract

Spinal cord stimulation (SCS) is a widely used clinical technique to treat ischemic pain in peripheral, cardiac and cerebral vascular diseases. The use of this treatment advanced rapidly during the late 80's and 90's, particularly in Europe. Although the clinical benefits of SCS are clear and the success rate remains high, the mechanisms are not yet completely understood. SCS at lumbar spinal segments (L2-L3) produces vasodilation in the lower limbs and feet which is mediated by antidromic activation of sensory fibers and decreased sympathetic outflow. SCS at thoracic spinal segments (T1-T2) induces several benefits including pain relief, reduction in both frequency and severity of angina attacks, and reduced short-acting nitrate intake. The benefits to the heart are not likely due to an increase, or redistribution of local blood flow, rather, they are associated with SCS-induced myocardial protection and normalization of the intrinsic cardiac nervous system. At somewhat lower cervical levels (C3-C6), SCS induces increased blood flow in the upper extremities. SCS at the upper cervical spinal segments (C1-C2) increased cerebral blood flow, which is associated with a decrease in sympathetic activity, an increase in vasomotor center activity and a release of neurohumoral factors. This review will summarize the basic science studies that have contributed to our understanding about mechanisms through which SCS produces beneficial effects when used in the treatment of vascular diseases. Furthermore, this review will particularly focus on the antidromic mechanisms of SCS-induced vasodilation in the lower limbs and feet.

1. Introduction

Spinal cord stimulation (SCS) delivers electrical impulses to different spinal segments via implanted electrodes. SCS has been used to treat various pain related diseases including ischemic pain for almost half century (Stojanovic and Abdi, 2006). Shealy was the first to use SCS to treat pain patients (Shealy et al., 1967). Currently SCS is the most common neuromodulatory treatment for ischemic pain and the overall beneficial effects last for at least 1 year in 80% of patients, and last for up to 5 years in 60% of patients (Deer and Raso, 2006). It is estimated that each year more than 14,000 SCS implantations are performed worldwide (Linderoth and Foreman, 2006). The beneficial effects of SCS when used to treat ischemic pain include pain relief, decreased infarction or ulcer size, decreased oxygen requirement and increased claudication distance. Clinical and basic studies indicate that these beneficial effects are mainly associated with increased blood flow or redistribution of blood flow to the ischemic area, and/or, normalization of the activity in the nervous system (Linderoth and Foreman, 1999; Erdek and Staats, 2003).

SCS is based on the gate-control theory published by Melzack and Wall in 1965 (Melzack and Wall, 1965), which partially explains the mechanism of SCS-induced pain relief. However, new theories have emerged from recent research that enables a more complete understanding of the mechanisms that produce the benefits of SCS for various organ systems. This review summarizes the multiple mechanisms of SCS employed to create beneficial effects on the vascular system in the lower limbs, feet, heart and brain. Moreover, when SCS is applied on C1-C2, T1-T2 and L2-L3, different mechanisms are engaged to produce the beneficial effects of SCS.

2. Effects of SCS on peripheral, cardio and cerebral vascular system

Ischemia typically results from obliteration of blood vessels due to the pathological changes of the tissues. An imbalance between oxygen supply and demand caused by an ischemic condition produces major metabolic changes in the tissue, and also ischemic pain in the different organs, including brain, heart and lower limbs and feet. Thus, SCS is applied at different spinal segments in order to provide benefit to a specific ischemic organ. SCS produces various benefits to the vascular system in the affected organs. SCS at lumbar spinal segments (L2-L3) produces vasodilation in the vasculature of the lower limbs and feet which is mediated by antidromic activation of sensory fibers and decreased sympathetic outflow. SCS at thoracic spinal segments (T1-T2) provides benefits including pain relief, reduction in frequency and severity of angina attacks, as well as reduced use of short-acting nitrate in patients with angina. There is at present no solid evidence that these benefits are due to an increase, or redistribution of local blood flow in heart, rather, these benefits are most likely the result of mechanisms that produce myocardial protection and normalize the intrinsic cardiac nervous system. SCS at cervical spinal segments (C1-C2) can result in an increase of cerebral blood flow, which is a result of a decrease in sympathetic activity, an increase in activation of vasomotor centers and a release of neurohumoral factors.

2.1 Effects of SCS on peripheral vascular system in the lower limbs and feet

2.1.1 Background

Many ischemic conditions in the limbs are due to peripheral arterial occlusive diseases (PAOD), which is caused by obstruction of blood flow into an arterial tree excluding the intracranial or coronary circulations (Garcia, 2006). PAOD is a major cause of disability, loss of work, and lifestyle changes in the United States (Garcia, 2006). The incidence of PAOD is 2 % in men under 50 years old and 5 % in men over 70 years old. However, the incidence of PAOD in women is in average delayed by ten years (Chochola and Linhart, 2006). It is estimated that PAOD affects and reduces the quality of life in about 2 million Americans. Furthermore, millions of Americans also suffer from PAOD-associated impairment of activity of daily living (ADL) and quality of life (QOL) (Marcoux et al., 1996; Hirsch et al., 2001; Golomb et al., 2006). The morbidity and mortality are relatively high because effective treatments are unavailable. SCS at the lower thoracic (T12) and higher lumbar spinal segments (L2-L3) is used to treat patients with PAOD in the lower limbs and feet. This treatment results in increased peripheral circulation in the limbs and feet. This outcome of SCS treatment in PAOD patients was first reported by Cook (Cook, 1976). Currently, SCS is usually considered only after vascular surgery and medications fail to prevent the progress of PAOD. Surprisingly the success rate of SCS-treated PAOD is greater than 70% (Cameron, 2004). The mechanisms of SCS-induced vasodilation in the lower limbs and feet are not yet completely understood. Two theories explaining the mechanisms of SCS-induced vasodilation have been proposed based on the results of three decades of clinical and basic science studies. One theory is that SCS decreases sympathetic outflow and attenuates constriction of arterial vessels; the alternative theory is that SCS antidromically activates sensory fibers and causes the releases of vasodilators.

2.1.2 Animal models and experimental designs

Sprague-Dawley (SD) rats have been used as animal models under normal physiological conditions to investigate the mechanisms of SCS-induced vasodilation in the lower limbs and feet (Linderoth et al., 1991 a, b, 1994, 1995; Croom et al., 1996, 1997 a, b, 1998; Tanaka et al., 2001, 2003 a, b, 2004; Wu et al., 2006 a, c, d, 2007). Details about the experimental methods are described in these articles. A small ball electrode is placed on the ipsilateral dorsal column near the spinal artery. The electrical stimulation parameters are 50 Hz with 0.2 ms duration with monophasic rectangular pulse. In earlier studies, constant voltage (Linderoth et al., 1991 a) and constant current (Croom et al., 1997) techniques are used for setting SCS stimulation parameters. In recent studies, the motor threshold (MT) is used to calculate stimulus intensity. MT is initially determined in each animal by slowly increasing the SCS current from zero until muscle contraction is observed (Tanaka et al., 2001). The contraction is a reflex response to stimulation of dorsal column fibers, i.e., primary afferents. Activation of these afferent fibers potentially could excite the motoneuronal pools that innervate muscles in the lower limbs (Gerasimenko et al., 2006). The experimental SCS (50 Hz; 0.2 ms, monophasic rectangular pulses), is performed at 30%, 60%, 90%, 300% or 10 times of MT (Tanaka et al., 2003 a; Wu et al., 2006). The lowest level of stimulation at 30% of MT is used because it was closest to the threshold of SCS that produced vasodilation. A stimulation level 60% of MT level is also used because it approximates the parameters of clinical applications of SCS (Linderoth et al., 1991 a, b, 1994). A stimulation level 90% of MT intensity is used because it is close to, but below MT. Stimulation levels at 3 and 10 times of MT are used to observe how SCS at high intensity stimulation affects the peripheral blood flow by mimicking traditional antidromic vasodilation (Bayliss, 1901). The effectiveness of SCS depends on the segments being stimulated and synaptic interaction. SCS at the lower cervical spinal segments such as C5-C6 is used to treat ischemic diseases, such as Raynaud's disease in the upper limbs (Robaina et al, 1989; Sciacca et al, 1998; Neuhauser et al, 2001). However, in patients with lower limb diseases, SCS at the upper lumbar spinal segments such as L2-L3 produced the largest increase in cutaneous blood flow in the lower limbs. SCS at the higher levels of spinal segments, such as T10, has been observed to decrease cutaneous blood flow in the hindpaws of rats (our observation). This observation is also consistent with the clinical findings of a reduction of peripheral blood flow when the stimulation is at segments above T10 in patients with PAOD (Ghajar and Miles, 1998). In animal studies, transection of T13, but not T10 spinal segment, abolishes vasodilation produced by SCS at L2 spinal segment (Barron et al, 1999). Also, when muscimol, an inhibitor of synaptic activity, is topically applied on the dorsal surface of the spinal cord, SCS effects on peripheral circulation are attenuated (Barron et al, 1999). These results support the theory that SCS-induced vasodilation is dependent on synaptic integration, but is independent of input from rostral spinal sites or supraspinal areas.

2.1.3 Antidromic mechanism

The idea of an antidromic mechanism for vasodilation was initially proposed by Bayliss (Bayliss, 1901). He observed that dorsal root stimulation at high intensity induced peripheral vasodilation mediated by thin fibers. This finding was also confirmed by the observation that a high intensity stimulation of dorsal roots provoked an increase in muscle blood flow (Hilton and Marshall, 1980; Groth, 1985). Foreman's group has investigated this antidromic mechanism over the past ten years, the results of which will be discussed below (Croom et al., 1996, 1997 a, b, 1998; Tanaka et al., 2001, 2003 a, b, 2004; Wu et al., 2006 a, c, d 2007 a, b).

The types of sensory fibers involved in SCS-induced vasodilation

Several studies have been performed to determine the types of sensory fibers involved in SCS effects on peripheral vasodilation. Application of high concentration of capsaicin (1%) on the tibial nerves in vivo blocked in C-fiber conduction and resulted in a reduced duration and amount of vasodilation induced by SCS at 90% and 10 times of MT, but not at 30 and 60% of MT (Tanaka et al., 2003 a). Antidromic compound action potentials (CAPs) of C-fibers in dorsal roots were only evoked by SCS ≥90% of MT, which indicates that SCS-induced vasodilation ≤60% of MT may be mediated via myelinated fibers, whereas vasodilation at ≥90% of MT may also involve unmyelinated C-fibers. Resiniferatoxin (RTX), an ultrapotent analog of capsaicin and transient receptor potential vanilloid receptor-1 (TRPV1) agonist (Zahner et al, 2003; Pan et al, 2003; Wu et al., 2006 b) applied intravenously as well as on the spinal cord, peripheral nerves and in the paw abolished vasodilation produced by SCS (Wu et al., 2006 a, c). Thus, these data indicate that SCS-induced vasodilation is predominantly mediated via TRPV1 containing sensory fibers in unmyelinated C-fibers or myelinated Aδ sensory fibers.

The role of vasodilators

Several vasodilators are contained in sensory endings and are released during SCS. CGRP and other vasodilators are co-localized in TRPV1 sensory containing terminals (Eguchi et al, 2004). The activation of TRPV1 and the subsequent depolarization of the sensory terminals caused the release of these vasodilators which enter the vascular smooth muscle layer (Caterina et al., 1997; Bernardini et al., 2004; Funakoshi et al., 2006). CGRP is one of the most powerful microvascular vasodilators (Brain et al., 1985). It is approximately 10 fold more powerful than prostaglandins and 100−1000 times more effective than other typical vasodilators such as, acetylcholine, adenosine and Substance P (SP) (Brain and Grant, 2004). CGRP plays a crucial role in producing vasodilation and maintaining low vascular resistance by binding to the CGRP-1 receptor (Jansen-Olesen et al., 2001; Brain and Grant, 2004,). CGRP 8−37, a classic antagonist of CGRP-1 receptor, has been used to block CGRP-induced vasodilation (Chiba et al., 1989). Intravenous or paw injection of CGRP 8−37 attenuates SCS-induced vasodilation at all intensities (Tanaka et al., 2001; Wu et al., 2006 c). This result suggests that CGRP binding CGRP-1 receptor plays a pivotal role in mediating SCS effects. However, adrenomedullin (ADM), another peptide from the calcitonin family, co-localizes with CGRP in some tissues, including perivascular nerves and dorsal root ganglia (Hobara et al., 2004). ADM is invloved in angiogenesis (Ribatti et al., 2005) and endothelial protection (Kato et al., 2005). ADM also can produce vasodilation by binding CGRP-1 receptor, although its vasodilation effect is relatively weaker when compared to CGRP (Aiyar et al., 1996; McLatchie et al., 1998; Hagner et al., 2002). Thus, ADM may at least be partially involved in SCS-induced vasodilation. Further studies are needed to determine the exact roles of ADM in SCS effects on ischemic diseases. Nitric oxide (NO) is considered to be another important component involved in SCS-induced vasodilation (Croom et al., 1997 b). Intravenous injection of non selected nitric oxide synthase inhibitors, N (omega)-nitro-L-arginine methyl ester (L-NAME) and N(G)-monomethyl-l-arginine (L-NMMA), decreased SCS-induced vasodilation (Croom et al., 1997 b). Local paw injection of L-NAME has also been shown to decrease vasodilation by SCS (Wu et al., 2007b). NO can be released either from TRPV1 containing nerve endings, or from endothelial cells after CGRP activates their intracellular pathways. In order to differentiate the sources of NO during SCS, a neuronal NOS (nNOS) inhibitor 4S)-N-(4-Amino-5[aminoethyl]aminopentyl)-N’-nitroguanidine, TFA, was directly injected into the paw. However, even a high dose of this neuronal NOS (nNOS) inhibitor did not inhibit SCS-induced vasodilation (Wu et al., 2007b). This indicates that NO is not released from nerve terminals, but instead may be released from endothelial cells during SCS. The peripheral pathways are summarized in Fig 1. Intravenous injection of this specific neuronal NOS (nNOS) inhibitor partially attenuated vasodilation produced by SCS (our unpublished data), suggesting that neuronal NOS may play a role in other tissues such as spinal cord. A previous study in dogs (Sanchez-Ledesma et al., 1990) also showed that, after 60 min of SCS, local arterial vasoactive intestinal peptide increases by 33%, and local arterial and venous histamine increase by 26 and 29%, respectively, but no difference was found in levels of SP.

Figure 1. The Summary of Antidormic Mechanisms of SCS-Induced Vasodilation in Limbs and Feet.

Figure 1

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The diagram summarizes the antidromic mechanisms that SCS activates TRPV1 containing sensory neurons. The neural information is transmitted from the site of stimulation in the spinal segments to the nerve endings in the peripheral tissues and results in the production and release of vasodilators, including CGRP. CGRP, the most powerful vasodilator, then binds its receptors in endothelial cells and their activation leads to the production and subsequent release of NO to vascular smooth muscle cells, which results in relaxation.

The roles of ERK and AKT

The central spinal terminals of TRPV1 containing sensory fibers in L 3−5 are necessary to produce SCS-induced vasodilation (Wu et al., 2006 a). However, it is unclear how SCS activates these terminals at the spinal level. Anatomically, these sensory central terminals are localized near lamina I and II spinal neurons of the dorsal horn (Sugiura et al., 1993). Activation of extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) in lamina I and II of the dorsal horn are significantly increased after SCS at 90% of MT in the rats (Wu et al., 2006 d). Moreover, local administration of U0126, an inhibitor of ERK kinase, and LY294002, an inhibitor of PI3K upstream of AKT onto the spinal cord significantly decreased SCS-induced vasodilation at 60% and 90% of MT (Wu et al., 2006 d). These results indicate that ERK and AKT play important roles in SCS-induced vasodilation. Other experiments have shown that during SCS the amount of GABA in the spinal cord is increased, while the amount of excitatory amino acids (EAA), glutamate and aspartate are decreased during SCS (Cui et al., 1997 a, b, 1998). It has been shown that substance P, N-methyl-D-aspartate (NMDA) receptors and non-NMDA receptors, are associated with antidromic activity in acute neurogenic inflammation evoked by intradermal injection of capsaicin (Lin et al., 1999, 2004). More research at the biochemical level of the spinal cord is necessary to identify how SCS activates TRPV1 containing sensory fibers.

Section summary

Current knowledge supports the antidromic hypothesis that, at the spinal L2−5 segments SCS activates interneurons containing ERK, AKT and possibly other intracellular signaling molecules, which subsequently stimulate spinal terminals of TRPV1 containing sensory fibers. The neural information is transmitted from the site of stimulation in the spinal segments to the nerve endings in the peripheral tissues and results in the production and release of vasodilators, including CGRP. CGRP, the most powerful vasodilator, then binds its receptors in endothelial cells and their activation leads to the production and subsequent release of NO to vascular smooth muscle cells, which results in relaxation. CGRP also binds to its receptors in vascular smooth muscle cells and activates intracellular signaling pathways, which also produce relaxation of vascular smooth muscle cells. The result is that relaxation of vascular smooth muscle cells results in a decrease in vascular resistance and an increase in local blood flow (Fig 1).

2.1.4 Sympathetic mechanism

It has been proposed that SCS-induced vasodilation may also occur via sympathetic mechanisms. Specifically, SCS suppresses sympathetic activity and subsequently produces marked vasodilation. This theory was proposed based on the results from the clinical observations that a sympathetic block or sympathectomy produced pain relief and vasodilation mimicking the effects of treatment with SCS (Augustinsson et al., 1985; Linderoth et al., 1991 a; Horsch et al., 2004). It is known that the activity of the sympathetic system regulates vascular tone in skin and muscle tissue via autonomic ganglia (Linderoth et al., 1994). Acetylcholine binds to postsynaptic nicotinic receptors and subsequently activates adrenergic receptors in the peripheral tissue, such as vascular smooth muscles. Stimulation of α1 and α2 – adrenoreceptors induces vasoconstriction via the contraction of vascular smooth muscle. In contrast activation of ß2- adrenoreceptors produces vasodilation through the relaxation of vascular smooth cells (Parkinson, 1990 a, b).

SCS–induced cutaneous vasodilation in the rat hindpaw at 66% of MT was abolished by complete surgical sympathectomy (Linderoth et al., 1991 a). Furthermore, the roles of cholinergic and adrenergic receptors in SCS-induced vasodilation were examined (Linderoth et al., 1994). Administration of ganglionic blocker, hexamethonium, or neuronal nicotinic ganglionic blocker, chlorisondamine, abolished the vasodilation produced by SCS. The adrenergic receptor blockers, phentolamine and prazosine in high doses also suppressed SCS-induced vasodilation. However, muscarinic receptor antagonists, pirenzepine and atropine, and the α2 – adrenoreceptor blocker, yohimbine did not alter the SCS effect (Linderoth et al., 1994). These results indicate that the vasodilatory effect of SCS is mediated by an inhibitory effect on peripheral vasoconstriction that is maintained by efferent sympathetic activity including nicotinic transmission in the ganglia and the postganglionic α1- adrenergic receptors. However, conflicting information exists regarding the importance of this mechanism in the peripheral actions of SCS. For example, a α2 agonist, clonidine in high doses suppressed SCS-induced vasodilation. Also some patients demonstrated vasodilation with SCS even after chemical or surgical sympathectomy (Meglio et al., 1986; Broseta et al., 1986; Jacobs et al., 1988). It should be noted that, in humans, sympathectomy is rarely total. Therefore some autonomic responsiveness to SCS may have remained intact.

2.1.5 The relative importance of antidromic and sympathetic mechanism

This section will discuss how the antidromic mechanism and a sympathetic mechanism may interact to produce vasodilation. An early study suggested that the antidromic mechanism did not contribute to vasodilation resulting from SCS. Dorsal root transection did not affect the increased blood flow following SCS at a low intensity in Albino rats (Linderoth et al., 1989). This result is incompatible with an antidromic mechanism. The importance of sympathetic mechanisms in SCS-induced vasodilation were generally supported by experiments conducted using SD rats living in the cold environment of northern Europe where the rats maintain high sympathetic nervous system activity (Linderoth et al., 1991 a, b, 1994, 1995). This relationship has been further investigated by using SD rats in the United States under controlled environmental conditions (Tanaka et al., 2003 b). In a 2003 study by Tanaka, the hindpaw was placed a cooling copper coil to produce local cooling (<25 degrees °C) or moderate local cooling (25−28 degrees °C), resulting in increased sympathetic activities (Freedman et al., 1992). Vasodilation produced by SCS was divided into early and late phases. SCS at all intensities (30%, 60%, and 90% of MT) produced vasodilation at the early phase of vasodilation in the cooled and the moderately cooled hindpaw. The late phase of vasodilation produced by SCS at 90% of MT in the cooled hindpaw was blocked by hexamethonium, a ganglionic blocker. However hexamethonium did not affect the early phase of vasodilation produced by SCS (Tanaka et al., 2003 b). In contrast, CGRP 8−37, a CGRP-1 receptor antagonist, abolished both the early and the late phase responses to SCS. The late phase of vasodilation produced by SCS at 90% of MT in the cooled hindpaw still existed after dorsal rhizotomy (Tanaka et al., 2003 b). The results indicate that SCS-induced vasodilation in the cooled hindpaw (<25 degrees °C) is mediated via both antidromic and sympathetic mechanisms. In contrast, the antidromic mechanism may predominate with moderate skin temperatures (25−28 degrees °C). Therefore, two complementary mechanisms may exist for SCS-induced vasodilatation. The balance of the dual mechanisms depends on the sympathetic activity level, SCS intensity, and individual patients or animal strains.

In addition to peripheral occlusive diseases, vasospastic diseases (mainly Raynaud's disease) also cause ischemic symptoms. Raynaud's phenomenon usually is triggered by cold temperatures, or by emotions such as stress and anxiety (Cooke and Marshall, 2005). The pathological mechanisms are related to the high level of sympathetic activity (Stallworth et al., 1981; Sakakibara et al., 2002; Cooke and Marshall, 2005) and low level of CGRP expression in the local sensory fibers (Mourad and Priollet, 1997; Bunker et al., 1996). The island skin flap animal has been used to mimic the vasospastic condition (Linderoth et al., 1995 b; Qi et al., 2002). In brief, a groin neurovascular flap that exposed the epigastric vessels was proposed in the rat in the supine position. To produce vasospasm, the isolated superficial epigastric artery was repetitively compressed to complete closure with two microforceps for 10 seconds (Linderoth et al., 1995 b). Preemptive SCS showed strong protective effects on the vasospasm (Linderoth et al., 1995 b). Furthermore, another study showed that preemptive SCS increased the survival rate of skin flaps rendered ischemic by occluding the blood supply to the tissue for as long as 12 hours (Gherardini et al., 1999). This cytoprotective effect was markedly reduced by concomitant administration of the CGRP-1 receptor antagonist CGRP 8−37 (Gherardini et al., 1999). Experimental flap survival was increased by the preoperative administration of antiadrenergic drugs such as guanethidine, reserpine, and 6-hydroxydopamine (Jurell and Jonsson, 1976). Therefore, in this pathological ischemic condition of vasospasm and critical ischemia, the dual mechanisms of the release of vasodilators by the antidromic activation of sensory fibers and the suppression of sympathetic activity are probably all involved in the prevention of vasospasm and in cytoprotection.

2.1.6 Other comments

PAOD is a multifactorial disease. In addition to atherosclerosis, multiple risk factors contribute to the complex pathological process of PAOD including genetics, obesity, diabetes mellitus, high blood cholesterol, hypertension and living environment (Garcia, 2006). Therefore, SCS treatment is likely to induce vasodilation in PAOD patients through multiple pathways (Fig 2). Besides these two classic hypotheses, other mechanisms are also potentially involved in SCS effects. First, the release of vasodilators and other peptides may improve endothelial function (Yu et al., 2007) and supress the formation of new atherosclerotic plaques (Kato et al., 2005). The role of endothelial cells and their contribution to the vasodilation effect of SCS are still unclear. New surgical techniques for denuding endothelial cells in peripheral arteries need to be established in order for further studies to be conducted. Second, the release of CGRP and possibly ADM during SCS may also have the ability to stimulate angiogenesis and thus contribute to the long-term effects of SCS (Jang et al., 2000; Nikitenko et al., 2000; Zudaire et al., 2003). Therefore, SCS may not only increase local blood flow in the ischemic area in the short term, but also rebuild new vessel systems to provide increased blood flow to the ischemic area over a long period. Third, opening, or/and rebuilding the arterial collaterals is proposed as an important treatment of PAOD, which compensates for the insufficient blood flow resulting from occluded arteries (Baklanov and Simons, 2003). Through this proposed mechanism, SCS is likely to stimulate and open arterial collaterals and provide extra blood flow to the ischemic area (our preliminary data & discussion with Dr. Li Linggen in the first affiliated hospital of Heilongjiang University of Chinese Medicine, P.R.China). Fourth, accumulating data from clinical studies also show that SCS has similar effects on vascular diseases in patients with, or without diabetes mellitus. Transcutaneous oxygen tension (TcPO2) changes were used as a predictive index of SCS therapy success (Petrakis and Sciacca, 1999, 2000). Thus, SCS has the potential benefit of repairing the damaged nerves and vessels caused by hyperglycemia (Wu et al., 2007a). Fifth, SCS is well known to reduce pain transmission (Linderoth and Foreman, 1999), which contributes to the relief of ischemic pain. Results from a clinical study show that opioid peptides are released during SCS. In that study, plasma Met-enkephalin increased during SCS, indicating an involvement of opioids in the regulation and improvement of the microcirculation by SCS (Fontana et al, 2004). However, clinically there is little or no evidence that opioids are involved in the SCS effects (Eliasson et al., 1998; Meyerson and Linderoth, 2000)

Figure 2. Potential Mechanisms of SCS-induced Vasodilation in the Limbs.

Figure 2

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The diagram illustrates that SCS –induced vasodilation may be mediated via 1) antidromic activity of TRPVR1 containing sensory fibers; 2) decrease of sympathetic outflow; and 3) electrical stimulation and opening of collaterals. In addition to vasodilation, the potential mechanisms for other SCS benefits including pain relief, endothelial protection and angiogenesis are also described.

2.2 Effects of SCS on cardiovascular system

2.2.1 Background

Refractory angina pectoris is one of the most common results of heart diseases, and is clinically characterized by discomfort in the chest, jaw, shoulder, back, or arm, which is typically aggravated by exertion or emotional stress (Gibbons et al., 1999). Vasospasm and vessel occlusion are two common mechanisms resulting in the decrease in blood supply to the heart. The imbalance between the supply and the demand of oxygen to the heart is crucial for the development of angina pectoris. More and more patients with chronic angina pectoris resist conventional treatments (Dejongste et al., 2004). SCS has been used to therapy-resistant angina pectoris since the 1980's (Murphy and Giles, 1987; Mannheimer et al., 1988; Augustinsson. 1989). Application of SCS at T1-T2 or higher spinal segments provides promising benefits in patients with angina pectoris. These benefits includes pain relief, reduction in both frequency and to some extent severity of angina attacks, and a reduced short-acting nitrate intake (Jessurun et al., 1996; Stojanovic and Abdi, 2002; Yu, et al, 2004; Chua and Keogh, 2005; Buchser et al., 2006;). Thus, SCS improves the quality of life in patients with angina pectoris by alleviating the symptoms (Yu, et al, 2004). Animal studies have been performed to explain the underlying mechanisms that contribute to pain relief and improved cardiac functions in human.

The mechanisms of SCS effects in heart are more complex and conflicting compared to SCS effects in the limbs and brain. Several hypotheses have been proposed based on animal models to interpret the SCS effects. SCS is suggested to have anti-anginal effects resulting from inhibition of nociceptive transmission (Chandler et al., 1993). Another theory is that SCS may cause a redistribution of the local blood flow and a decrease in the coronary oxygen demand (Eliasson et al., 1993; Jessurun et al., 1996; Linderoth and Foreman, 1999). Recently, it was proposed that SCS stabilizes the intrinsic cardiac nervous system and improves cardiac function (Foreman et al., 2000; Armour et al., 2002; Cardinal et al., 2006). Pre-emptive SCS is likely to protect myocardium from effects of critical ischemia (Southerland et al., 2006). Importantly, there is no solid evidence that SCS has the capability to augment local blood flow in the heart, which is different from the SCS effects on the limbs and brain (Norrsell et al., 1998; Kingma et al 2001).

2.2.2 Animal models and experimental designs

Several different coronary ischemic models have been established in order to study SCS effects on the heart (Kingma et al 2001; Cardinal et al, 2006; Southerland et al., 2006). Acute complete occlusion of the left anterior descending coronary artery (LAD) in dogs (Kingma et al 2001), rabbits (Southerland et al., 2006) or rats (Pirat et al., 2007) have been used as an acute ischemic model. A chronic ischemic model has also been established by implanting an ameroid constrictor around proximal left circumflex coronary artery (Cardinal, et al., 2004). Since the material of the constrictor absorbs fluid and swells slowly in 3−4 weeks (Tomoike et al., 1983), the obstruction to blood flow was produced very slowly and created a relatively chronic ischemic condition in the heart. Also different stressors, such as transient bouts of rapid ventricular pacing and angiotensin II administration, are used to activate the intrinsic cardiac nervous system and mimic clinical heart diseases (Cardinal, et al., 2004). In addition to these models, mediastinal nerve stimulation has been reported to induce bradycardias and atrial tachyarrhythmias in dogs (Cardinal, et al., 2006). 90% of MT (50 Hz, 0.2-ms duration) is the acceptable intensity for SCS studies in the heart (Kingma et al 2001; Cardinal, et al., 2006), and the quadrupolar electrode catheter is commonly used (Cardinal, et al., 2006). T1-T2 spinal segments are the most common and optimal places to be stimulated and the electrode is placed slightly to the left of midline (Cardinal, et al., 2006). However, SCS applied at segments higher than the T1 level also provides some cardioprotection (Gonzalez-Darder et al., 1998; Southerland et al., 2006).

2.2.3 Mechanisms for changes in blood flow

The effect of SCS on cardiac blood flow is still controversial. Unlike the obvious increase in blood flow elicited by SCS in the limbs and brain, few studies report that SCS augments coronary or cardiac blood flow, or redistributes myocardial blood flow (MBF). Effects of SCS on changes of MBF in patients with angina pectoris has been investigated by using positron emission tomography (PET) (Mobilia et al., 1998). The results showed that SCS increased mean MBF and redistributed MBF between the regions with low or normal basal flow and the regions with high basal flow. Also, SCS was reported to improve angina pectoris with a concomitant improvement of myocardial perfusion in cardiac syndrome X (Jessurun et al., 2003). However, another clinical study obtained the opposite results (Norrsell et al., 1998) and found that the anti-ischaemic effect of SCS is independent of an increase in coronary flow velocity. In an experimental animal study, Kingma et al., (2001) investigated this hypothesis by establishing acute complete occlusion of LAD in the dogs. The results showed that SCS did not increase local flow in the myocardium or redistribute blood flow in the non-ischemic or ischemic myocardium. However, a limitation of this study is that occlusions were performed on normal hearts. To make the study more accurate, the experiment should be performed in heart with an ischemia and/or infarction. A clinical study also showed that in the long term, SCS resulted in a decrease of myocardial ischemia. The effect might be due to the formation of better coronary collateralisation because of enhanced physical activity of the patients, instead of a direct effect of SCS (Diedrichs et al, 2005).

Overall, in contrast to the effects of SCS on the peripheral circulation in the limbs, SCS does not produce vasodilation in the cardiovascular system of animals with a normal heart (Kingma et al, 2001). However, neuropeptides including CGRP and NO, as well as TRPV1 containing sensory fibers exist and play important roles in the regulation of cardiovascular system (Ferdinardy et al., 1997; Chottova Dvorakova et al., 2005; Funakoshi et al., 2006; Zyara et al., 2006; Ye et al., 2006). One explanation is that SCS does not activate TRPV1 containing sensory fibers resulting in vasodilation, but stimulates other types of fibers that regulate the cardiac nervous system (see section 2.2.4). Another theory is that SCS may produce release of CGRP strongly affects local circuit neurons and myocardium, but not blood vessels. This may be due to location of nerve endings or to the amount of CGRP released. Therefore, SCS does not produce vasodilation, but is able to adjust the intrinsic cardiac nervous system and protect the heart. Further studies are necessary to elucidate this question.

2.2.4 Intrinsic cardiac nervous system related mechanism

The intrinsic cardiac nervous system is located in the cardiac ganglion plexi of epicardial fat pads adjacent to and within the myocardium (Ardell, 2004). This system includes parasympathetic efferent, sensory afferent, sympathetic efferent and interconnecting local circuit neurons. Interconnecting local circuit neurons have the abilities not only to interact locally, but also to connect with neurons in higher centers resulting in the coordination of regional cardiac function. This population of neurons provides rapid and timely reflex coordination of autonomic neuronal outflow to the heart (Armour, 1999). Clinical observations show that SCS reduces the magnitude of ST segment changes in the electrocardiogram (ECG) induced by exercise and rapid cardiac pacing (Sanderson et al., 1992). SCS is considered to improve cardiac function to a considerable degree by regulating the intrinsic cardiac nervous system (Linderoth and Foreman et al., 2006). Several studies, especially from International Working Group on Neurocardiology (IWGN) support this theory. Bradycardias and atrial arrhythmias can be neuronally induced by mediastinal nerve stimulation in dogs (Cardinal et al., 2006). SCS significantly suppresses these arrhythmias provoked by ischemia (Issa et al., 2005; Cardinal et al., 2006). This effect is blocked after bilateral stellectomy (Cardinal et al., 2006). These data indicate that SCS prevents the induction of atrial arrhythmias induced by excessive activation of intrinsic cardiac neurons (mediastinal nerve stimulation), which is dependent on the integrity of nerves coursing through the subclasvian ansae and stellate ganglia (Cardinal et al., 2006). In another study, SCS reduced the ST segment elevations in an ischemic challenged heart. Ameroid constrictors were implanted around the left circumflex coronary artery (LCx) in canines to mimic the chronic ischemic heart (Cardinal et al., 2004). ST segment displacements were triggered by collateral-dependent myocardium in response to two stressors, transient bouts of rapid ventricular pacing (240/min for 1 min) and angiotensin II administration (100 μg/ml. 0.4 ml/min) to the intrinsic neurons of the right atrial ganglionated plexus (Cardinal et al., 2004). SCS significantly attenuated the increased ST elevation induced by the chronically activated intrinsic interneurons. However SCS did not reduce the increased ST elevation induced by the metabolically determined effects of ventricular rapid process (Cardinal et al., 2004). Importantly, SCS blocked the chemical activation of the intrinsic cardiac nervous system, supporting the theory that SCS improves cardiac function resulting from the normalization of intrinsic cardiac nervous system. In the other words, SCS stabilizes the activity of the intrinsic cardiac nervous system that is typically activated by ischemia. Modulation of sympathetic activity and sensory fibers by SCS are likely to be involved in this mechanism (Linderoth and Foreman, 2006), although the details are still unclear.

2.2.5 Pain suppression mechanisms

The gate-control theory (Melzack and Wall, 1965) supports the general concept that SCS may have inhibitory effects on nociception, which can relieve different kinds of pain, including ischemic pain in the heart. A previous study showed that in anaesthetized monkeys, SCS reduced the number of action potentials of spinothalamic tract neurons evoked by electrical stimulation of cardiopulmonary sympathetic afferent fibers. Furthermore SCS also decreased neuronal activities evoked by intracardiac injection of bradykinin, a mediator of inflammation (Chandler et al., 1993). This study indicates that SCS may also reduce pain transmission via a decrease in the firing of spinothalamic tract cells. However, it is unclear if the suppression of spinothalamic tract activities is a direct effect or results from a reduction in nociceptive information transmitted by afferent fibers.

2.2.6 Protective mechanisms in the myocardium

The results of animal studies lead to the idea that SCS may produce protective changes in the myocardium that allow the heart to resist damage under circumstances producing critical ischemia. SCS has been reported to produce the local release of catecholamine in the myocardium (Armour et al., 2002; Ardell et al., 2005). Catecholamines have also been reported to protect heart from transient myocardial ischemia-induced apoptosis mediated by α1 –PKC pathway and ß-PKA pathway (Broadley and Penson, 2004;). A recent study also reported that this cardioprotection was dependent on cardiac adrenergic efferent neurons (Southerland et al., 2006). Other neuropeptides, such as NO (Sanada and Kitakaze, 2004) and beta-endorphin (Eliasson et al., 1998) are potentially released during SCS and also may prevent myocardial ischemia. The overall potential mechanisms of SCS effects on heart are summarized in Fig 3.

Figure 3. Potential Mechanisms of SCS-improved Heart Function.

Figure 3

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The diagram illustrates that SCS-improved Heart Function may be due to 1) an increase or redistribution of blood flow; 2) regulation of the intrinsic cardiac nervous system; 3) release of neuropeptides; and 4) suppression of nociceptive transmission.

2.3 Effects of SCS on cerebral vascular system

2.3.1 Background

Hosobuchi was the first to report that SCS at cervical level, or cervical spinal cord stimulation (cSCS), produced a significant increase in cerebral blood flow (CBF) (Hosobuchi, 1985). Since then, the multiple clinical and basic studies have confirmed this effect. Effects of cSCS on the cerebral vascular system include an increase in CBF (Meglio et al., 1991 a; Ebel et al., 2001; Robaina et al., 2004; Karadag et al., 2005) combined with a decrease in cerebral vascular resistance and an increase in blood flow velocity (Meglio et al., 1991 b), leading to an enhancement of the local-regional delivery of oxygen (Clavo et al., 2002, 2003, 2004), Further effects of cSCS on the cerebral vascular system also include a decrease in induced vasospasms (Visocchi et al., 2001; Gurelik et al., 2005) and an improvement of neurological dysfunction (Gurelik et al., 2005), a modification of glucose metabolism (Momose et al., 1989; Clavo et al., 2006), and the prevention of early spasm due to subarachnoid hemorrhage (SAH) (Visocchi et al., 2001). cSCS effects on cerebral vasodilation depend on a decrease of sympathetic tone (Sagher et al., 2000; Patel et al., 2003), activation of vasomotor centers (Sagher et al., 2000; Patel et al., 2004) and release of neurohumoral factors (Hosobuchi, 1985; Goksel et al., 2001).

2.3.2 Animal models and experimental designs

The animals used for experimental models for the experimental studies include rats, goats, dogs, cats and rabbits. Rats are used to study the cSCS effects under the normal physiological conditions (Sagher et al., 2000, 2003; Patel et al., 2003). The effects of cSCS in pathological conditions are studied with several vasospasm models that have been established in the larger animals such as rabbits (Visocchi et al., 1994; Goksel et al., 2001) and cats (Matsui et al., 1989; Isono et al., 1994). Cerebral ischemia can be induced by cerebral vasospasm after SAH as described by Karadag (Karadag et al., 2005) and Goksel (Goksel et al., 2001). In brief, fresh autologous blood (1 ml/Kg) from each animal's femoral artery was injected into cisterna magna (CM). The locations of cSCS can range from C1 to C6 and the optimal placements of the stimulating electrode is on segments C1-C3 (Patel et al., 2003; Goksel et al., 2001; Sagher et al., 2000). It showed that CBF was increased by more than 80% above baseline with the amplitude of 1.5 mA (Zhong et al., 2004). The optimal pulse width and frequency of cSCS was found to be 0.25 ms, and 50 Hz. A persistent increase in CBF can be produced when applying cSCS for up to 20 minutes. In another study in cats, cSCS at a 4V-stimulus amplitude (25 Hz and 0.1 msec) provided the appropriate microcirculatory enhancement without any harmful effects, and this was sustained 30 min after SCS (Inoue et al., 2000).

2.3.3 Sympathetic mechanisms

Sagher was the first to assess the role of sympathetic tone in cSCS-induced cerebral vasodilation (Sagher et al., 2000), although the earlier studies suggested this mechanism (Broseta et al., 1994; Isono et al., 1994; Visocchi et al., 1994). Intravenous administration of hexamethonium (10 mg/Kg) prior to the initiation of cSCS in the rats abolished the cSCS-induced cerebral vasodilation (Sagher et al., 2000). Another study also showed that cSCS-induced cerebral vasodilation was abolished by both a high-dose of hexamethonium (20 mg/Kg) and prazosin (a selective α-1 receptor blocker, 1 mg/Kg) (Patel et al., 2003). Idazoxan (a selective α-2 receptor blocker) and propranolol (a non-selective ß blocker) did not attenuate the cSCS effect (Patel et al., 2003). However a controversial study showed that cSCS-induced cerebral vasodilation is partially attenuated by propranolol (Garcia-March et al., 1989). Overall sympathetic tone is likely to play an important role in cSCS-induced cerebral vasodilation and this mechanism is mainly mediated by α-1 adrenergic receptors (Patel et al., 2003).

2.3.4 Vasomotor mechanisms

Transection at the spinal cervicomedullary junction significantly attenuated the cSCS-induced cerebral vasodilation, indicating that the cSCS effect may involve supraspinal mechanisms (Sagher et al., 2000). In another study, spinalization, but not resection of the superior cervical ganglion (SCG), abolished cerebral vasodilation produced by cSCS (Patel et al., 2004). The data support the idea that a vasomotor mechanism in the brainstem is crucial in the production of cSCS-induced cerebral vasodilation. Another study indicated that cSCS may activate supraspinal vasomotor centers including the ascending reticular activating system, hypothalamus, thalamus, cingulate gyrus and frontal cortex (Yamaguchi et al., 1995). It is known that the vasomotor centers and their nuclei are implicated in the regulation of CBF. Electrical stimulation of the cerebellar fastigial nucleus can lead to a significant increase in CBF (Mraovitch et al., 1986; Takahashi et al., 1995), which is mainly mediated by rostral ventrolateral nucleus in the medulla (Chida et al., 1990). Therefore, cSCS-induced cerebral vasodilation may initially activate vasomotor centers that include the cerebellar fastigial nucleus and rostral ventrolateral medulla nucleus via ascending spinocerebellar pathways (Patel et al., 2004. Another related theory is that functional activation of the frontal lobe by the ascending reticular pathways mediated via the thalamo-cortical projections during cSCS, is also associated with cSCS-induced cerebral vasodilation (Mazzone et al., 1995, 1996).

2.3.5 Neurohumoral mechanisms

The release of neurohumoral factors is another potential mechanism of cSCS-induced cerebral vasodilation (Hosobuchi, 1985). Indomethacin, a cyclooxygenase inhibitor, partially blocks the effect of cSCS (Hosobuchi, 1985). The role of NO synthase in cSCS-induced cerebral vasodilation during a cerebral vasospasm was investigated in the albino rabbits (Goksel et al., 2001). After the intracisternal injection of L-NAME, cSCS still produced cerebral vasodilation. However, this vasodilation was smaller when compared to the vasodilation produced by cSCS without L-NAME administration (Goksel et al., 2001). Therefore, NO, a basic mediator of vasodilation, is likely to be involved in cSCS-induced cerebral vasodilation. However this study did not determine whether NO synthase was from endothelial NOS, or the neuronal NOS that likely comes from nonadrenergic-noncholinergic nerve fibers (Nozaki et al., 1993). CGRP is another vasodilator that potentially contributes to cerebral vasodilation produced by cSCS in the same way that it contributes to SCS-induced vasodilation in the limbs (Croom et al., 1997). Immunochemical studies show that CGRP containing nerves innervate the cerebrovascular tree (Edvinsson et al., 1987, 1995; Suzuki et al., 1989). Furthermore, stimulation of trigeminal ganglion induced vasodilation mediated by these CGRP containing nerves (Escott et al., 1995). TRPV1 is widely expressed in several brain nuclei and human brain endothelial cells (Mezey et al., 2000; Golech et al., 2004). The studies of immunofluorescence show a high degree of colocalization of TRPV1 with CGRP and SP in the brain neurons, such as those in trigeminal ganglionic neurons (Bae et al., 2004) and corneal neurons (Murata, and Masuko, 2006). Recently, TRPV1 has been shown to be associated with cSCS-induced cerebral vasodilation (Yang et al., 2007). Thus, it is very likely that activation of TRPV1 and release of CGRP during cSCS, is partially involved in cSCS-induced vasodilation. Other vasodilators, such as histamine (Garcia-March et al., 1989) and vasopressin, are possibly involved in this process.

In addition, as we discussed for SCS-induced vasodilation in the lower limbs and feet (2.1.6), cSCS could potentially stimulate and open arterial collaterals of cerebral vascular systems, which could subsequently produce vasodilation. The overall potential mechanisms of the effects of SCS on the cerebral vascular system are summarized in Fig 4. The experimental findings of increased cerebral blood flow and prevention of vasospasm have hitherto, surprisingly, resulted in very few clinical studies mostly in comatose or vegetative patients after vascular catastrophes. (Momose et al., 1989; Funahashi et al., 1989; Kuwata 1993; Simpson 1997).

Figure 4. Potential Mechanisms of SCS-induced Vasodilation in Brain.

Figure 4

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The diagram illustrates that SCS –induced vasodilation may be related to 1) decrease of sympathetic outflow; 2) regulation of vasomotor center; 3) electrical stimulation and opening of collaterals; and 4) local release of neurohumoral factors. Additionally the release of neurohumoral factors may contribute to endothelial protection and angiogenesis.

3. Summary

In Summary, the effects of SCS on the vascular system are complex and involve multiple mechanisms (Table 1). Based on current knowledge, antidromic activation of sensory fibers and the subsequent release of vasodilators are the most important mechanisms for producing the benefits of SCS at L2-L3 in treatment of PAOD. The benefits to the heart from SCS at T1-T2 to heart are mostly likely due to a normalization of the intrinsic cardiac nervous system. The vasodilation of the cerebral vascular system produced by SCS at C1-C2 may largely be mediated by a suppression of sympathetic activity. Further studies are necessary in order to elucidate the profound mechanisms of SCS effects on the vascular system.

Table 1. The Summary of Different Mechanisms of SCS Effects on Peripheral, Cardiovascular and Cerebral vascular systems.

The table illustrates the different mechanisms regarding SCS effects on different organs: 1) effects of SCS at C1-C2 on cerebrovascular system are associated with the decrease of sympathetic outflow and activation of TRPV1; 2) effects of SCS at T1-T2 on cardiovascular system are largely dependent on adjusting intrinsic cardiac nervous system potentially via sympathetic and sensory neurons; 3) effects of SCS at L2-L3 on peripheral vascular system is due to antidromic activation of TRPV1 containing sensory neurons and a decrease of sympathetic outflow. Symbols explanation: + represents a positive relationship between SCS effects and one of mechanisms; ? represents an unproven relationship.

SCS Targeted Tissues Mechanisms
Sensory fibers Sympat hetic outflow CGRP TRPV1 NO other
C1-C2 Brain Vasodilation/Ischemia ? + ? + + Brain nucleus (+)
C1-C2 T1-T2 Heart Improved heart function/Angina pectoris + + ? ? ? Intrinsic cardiac nervous system (+)
L2-L3 Lower limbs Vasodilation/Ischemia + + + + + ERK and AKT phosphorylation in spinal cord (?)
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Other future studies should be focused on the effect of SCS on endothelial cells. Endothelial dysfunction is a critical pathologic process that can reduce vasodilation and form a proinflammatory and prothrombic condition. Endothelial dysfunction is closely related to the pathological process in most vascular diseases. It is thought that the release of neuropeptides during SCS may have beneficial effects on endothelial cells. However the effects of SCS on the prevention and recovery from endothelial dysfunction have not been studied.

Current experiments have concentrated on the mechanisms related to relative short duration (1−30 min) of SCS treatment in vascular diseases. However, mechanisms involved in producing effects in the vascular system accompanying chronic SCS treatment are still completely unknown. Thus, future experiments should include the development of pathological ischemic animal models with chronically implanted electrodes on the spinal cord for use in the long-term investigation of SCS and its effects on angiogenesis and the vascular system.

With the exception of the heart, the SCS effects on the vascular system of visceral organs, such as gastrointestinal tract, still remain unknown. Therefore, a significant amount of research is necessary in order to elucidate on the effects of SCS on the vascular system of visceral organs.

We believe that the clinical efficacy of SCS combined with a better understanding of the basic mechanisms of SCS effects on the vascular system will lead to increased and effective use of SCS in the treatment of properly screened patients who suffer from cerebral, peripheral, and cardiovascular diseases.

Acknowledgement

We are grateful to Dr. Xiaoli yang (Xi'an Jiaotong University), Chao Qin and Jay P. Farber (The University of Oklahoma Health Sciences Center) for their excellent advice during the preparation of this manuscript. We also thank Brooke Stephenson (The University of Oklahoma Health Sciences Center) for the comments to this manuscript. This review study is supported by NIH grant HL075524 & NS35471 (R.D.F), 2005 University of Oklahoma Health Sciences Center Graduate Student Association Research Grant (M.W) and American Heart Association (AHA) Predoctoral Fellowship 0615642Z (M.W).

Footnotes

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