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Published in final edited form as: Respir Physiol Neurobiol. 2017 Oct 23;256:15–20. doi: 10.1016/j.resp.2017.10.005

Intermittent but not sustained moderate hypoxia elicits longterm facilitation of hypoglossal motor output

Julia ER Wilkerson 1,3, Michael Devinney 1,4, Gordon S Mitchell 1,2
PMCID: PMC6768075  NIHMSID: NIHMS1051028  PMID: 29074449

Abstract

Phrenic long-term facilitation (pLTF) is a form of serotonin-dependent respiratory motor plasticity induced by moderate acute intermittent hypoxia (AIH), but not by moderate acute sustained hypoxia (ASH) of similar cumulative duration. Thus, moderate AIH-induced pLTF is sensitive to the pattern of hypoxia. On the other hand, pLTF induced by severe AIH protocols is neither pattern sensitive nor serotonin dependent (it converts to an adenosine-dependent mechanism). Although moderate AIH also induces hypoglossal LTF (hLTF), no data are available concerning its sensitivity/insensitivity to the pattern of hypoxia. Since hLTF following moderate hypoxia is serotonin-dependent, we hypothesized that hLTF is pattern-sensitive, similar to serotonin-dependent pLTF. Integrated hypoglossal nerve activity was recorded in urethane-anesthetized, vagotomized, paralyzed, and ventilated rats exposed to isocapnic AIH (3, 5 min episodes of 11% O2) or ASH (a single 25 min episode of 11% O2). Similar to previous studies of pLTF, hypoglossal motor output was elevated for more than 1 h following AIH (50 ± 20%, P < 0.01), but not ASH (−6 ± 9%, P > 0.05). Frequency LTF was not observed following either hypoxic exposure. Thus, in agreement with our hypothesis, hypoglossal LTF following moderate AIH is pattern-sensitive, similar to phrenic LTF.

Keywords: plasticity, hypoxia, pattern, control of breathing

Introduction

Patterned stimulation is often more effective than continuous stimulation at inducing plasticity in the central nervous system. For example, stimulus presentations spaced over time are more effective at inducing long term memory formation versus an equal duration continuous presentation (Ebbinghaus, 1913; Beck et al., 2000; Sutton et al., 2002; Cepeda et al., 2006). This phenomenon, known as the “spacing effect,” is expressed widely throughout the animal kingdom, and has been extensively studied in several animal models and humans because of its potential utility in education (Kerfoot, 2010), psychology (Goverover et al., 2009b), advertising (Janiszewski et al., 2003; Appleton‐Knapp et al., 2005) and physical rehabilitation (Goverover et al., 2009a). Consistent with the spacing effect in learning and memory, patterned stimulation (intermittent vs. continuous) is also more effective at eliciting synaptic plasticity in the nervous system. For example, intermediate-term memory formation and synaptic facilitation in Aplysia (Mauelshagen et al., 1998; Sutton et al., 2002), and hippocampal long-term potentiation in rodents (Kauer, 1999; Nguyen et al., 2000; Scharf et al., 2002) exhibit pattern sensitivity, with intermittent more effective than continuous stimulus presentations. Despite its importance to neuroplasticity, mechanisms giving rise to pattern sensitivity are not well known.

Some forms of hypoxia-induced respiratory motor plasticity exhibit clear pattern sensitivity (Baker & Mitchell, 2000; Wilkerson et al., 2008). For example, serotonin-dependent phrenic long-term facilitation (pLTF) can be elicited by moderate acute intermittent (AIH), but not moderate acute sustained hypoxia (ASH) of similar cumulative duration (Mitchell et al., 2001; Baker & Mitchell, 2000). Both severe intermittent and sustained hypoxia also elicit pLTF, although this form of pLTF is mediated by a distinct, adenosine-dependent mechanism (Nichols et al., 2012; Devinney et al., 2016). While episodic spinal serotonin receptor activation is required to elicit phrenic motor facilitation in rats, a single, larger serotonin injection fails to elicit the response (MacFarlane & Mitchell, 2009a). Further, whereas intermittent but not sustained serotonin receptor activation elicits phrenic long-term facilitation in neonatal brainstem-spinal cord preparations, similar pattern sensitivity is not observed in inspiratory intercostal activity (Lovett-Barr et al., 2006). Thus, all forms of respiratory motor plasticity do not exhibit similar pattern sensitivity to the inducing stimulus.

Another form of hypoxia-induced respiratory motor plasticity is hypoglossal long-term facilitation (hLTF; Bach and Mitchell, 1996). Similar to pLTF, hLTF is expressed as a progressive increase in hypoglossal motor output induced by moderate AIH (Bach & Mitchell, 1996; Baker-Herman and Strey, 2011). Hypoglossal LTF might stabilize the upper airways, maintaining upper airway patency during sleep (Fuller, 2005; Mahamed and Mitchell, 2007; Baker-Herman and Strey, 2011). Thus, greater understanding of distinctions between the mechanisms giving rise to pLTF versus hLTF could lead to new therapeutic approaches that minimize certain forms of obstructive sleep apnea (Baker-Herman and Strey, 2011). However, little is known concerning similarities and differences in the mechanisms of pLTF and hLTF, and there are no reports concerning pattern-sensitivity of hLTF with moderate hypoxia. Here, we demonstrate that hLTF exhibits pattern sensitivity, similar to moderate AIH-induced pLTF.

Materials and Methods

Experiments were performed on 3–5 month old male Sprague-Dawley rats (colony PO4, Charles River Inc., Wilmington, MA). Rats were individually housed in a controlled environment (12h light/dark cycle), with food and water ad libitum. The University of Wisconsin, School of Veterinary Medicine Animal Care and Use Committee approved all protocols.

Surgical Preparation and Nerve Isolation.

Rats were initially anesthetized in a closed chamber containing isoflurane followed by isoflurane administration through a nose cone (3.0 – 3.5% in 50% O2, balance N2). The trachea was cannulated to enable pump-ventilation (tidal volume, 2 – 2.5 mL; FIO2 = 0.50; Rodent Respirator model 682, Harvard Apparatus, South Natick, MA). A bilateral vagotomy was performed at the mid-cervical level to prevent entrainment of respiratory motor output with the ventilator. Catheters were placed into the tail vein for fluid administration (1:11 by volume NaHCO3:lactated Ringer’s; 2.5 mL/hr) and the femoral artery for blood pressure measurement and to draw blood samples for blood gas analysis. Body temperature was maintained at 37.5 ± 1.0 °C using a rectal probe and custom-designed heated table. The left hypoglossal nerve was isolated using a dorsal approach, cut distally, desheathed and placed on a bipolar silver electrode. Rats were slowly converted to urethane anesthesia (1.6 g/kg, i.v.) and then paralyzed with pancuronium bromide to prevent spontaneous breathing movements (2.5 mg/kg, i.v., supplemented as necessary). End-tidal CO2 was measured throughout the experiment using a flow-through capnograph (Capnogard, Model 1265, Novametrix; Wallingford, CT) with sufficient response time to measure expiratory gases in rats.

Experimental Protocols.

The CO2 apneic threshold was determined by decreasing CO2 levels and/or increasing the ventilator rate until nerve activity ceased. Inspired CO2 levels were then increased; the end-tidal CO2 at which phrenic activity resumed was taken as the recruitment threshold (Mahamed & Mitchell, 2007). End-tidal CO2 levels were then set 1–2 mmHg above the recruitment threshold. A stable hypoglossal neurogram was established and an initial blood sample was taken to establish baseline PaO2, PaCO2, pH, and base excess values (0.3 ml in 0.5 ml heparinized glass syringe; ABL-500, Radiometer, Copenhagen, Denmark; unused blood was returned to the animal). Rats were given 3, 5-min episodes of hypoxia (i.e., AIH; FIO2 = 0.11 ± 0.1, PaO2 = 39 ± 1 mmHg), separated by 5 min of baseline conditions (FIO2 = 0.5, PaO2 > 250 mm Hg), or a single, cumulative 25-min hypoxic episode (i.e., ASH; FIO2 = 0.11 ± 0.1, PaO2 = 38 ± 1 mmHg). Hypoglossal activity was monitored 60 min post-hypoxia to determine LTF magnitude. Arterial blood samples were drawn and analyzed during the final minute of the first hypoxic episode, and 15, 30 and 60 min after the final hypoxic episode. Additional rats that did not receive hypoxia (time controls) were used to verify the stability of nerve output over a similar time period in this preparation. Throughout the protocol, isocapnic conditions (± 1 mmHg from baseline PaCO2) were maintained by adjusting ventilator frequency and/or inspired CO2.

Electrophysiological methods.

Hypoglossal nerve activity was amplified (x 10,000), band pass filtered (100 Hz to 10 kHz; Model 1700, A-M Systems, Inc., Carlsborg, WA), and integrated (time constant = 50 ms, Model MA-821RSP, CWE Inc., Ardmore, PA). Integrated signals were digitized and processed with commercially available software (WINDAQ software, DATAQ Instruments, Akron, OH). Peak integrated hypoglossal burst amplitude, burst frequency, and mean arterial blood pressure were calculated over a 60 second period just prior to the first hypoxic episode (baseline), at the end of the first hypoxic episode or the equivalent time point during sustained hypoxia (short-term hypoxic response), and 30 and 60 min post-hypoxia. Data were included in the analysis only if isocapnic conditions were successfully maintained. Amplitude data are expressed as the change in hypoglossal burst amplitude, expressed as a percent change from baseline values. Frequency data are reported as a change from baseline in bursts per minute (delta burst frequency). Data were compared using a one-way ANOVA or two-way ANOVA with repeated measures design as applicable (Fisher LSD post-hoc test; SigmaStat 2.03, SPSS Inc., Chicago, IL).

Results

Physiological variables

No significant differences were observed in the CO2 recruitment threshold for rats treated with (IH: 41 ± 1 mmHg, n=9; SH: 40 ± 1 mmHg, n=14) or without hypoxia (42 ± 1 mmHg, n=14; p > 0.05). Under baseline conditions, mean arterial blood pressure was not different between treatment groups (IH: 112 ± 5 mmHg, SH: 110 ± 4 mmHg; Table 1; p > 0.05), or time controls that did not receive hypoxia: (112 ± 5 mmHg; Table 1, p > 0.05). Similar to other studies from our laboratory, mean arterial blood pressure significantly decreased during the hypoxic stimulus versus baseline (IH: 62 ± 4 mmHg, SH: 65 ± 7 mmHg; p < 0.05), but not in time controls (112 ± 5 mmHg; Table 1, p > 0.05). We did not observe significant changes in mean arterial blood pressure at 30 min post-hypoxia in any group; however, small but significant decreases were found at the 60 min time point in the AIH (105 ± 4 mmHg), ASH (100 ± 3 mmHg), and time control (105 ± 5 mmHg) (Table 1, p < 0.05). No significant treatment effects were found between groups at any time for mean arterial blood pressure (p > 0.05). PaCO2 was successfully maintained within 1 mmHg of the baseline value throughout experimental protocols. Thus, changes in hypoglossal burst amplitude or frequency were not caused by changes in arterial PCO2 from baseline values.

Table 1. Temporal changes in mean arterial blood pressure (MABP), PaCO2, and PaO2 in rats.

Relative to baseline, mean arterial blood pressure (MABP), arterial partial pressure of CO2 (PaCO2), and arterial partial pressure of O2 (PaO2) were not significantly different over time in rats that did not receive hypoxia (p > 0.05). As expected PaO2 significantly decreased during hypoxia exposure (P < 0.05), but returned to baseline values following exposure. Rat groups treated with intermittent or sustained hypoxia showed similar significant decreases in MABP during hypoxia (p < 0.05) and small but significant decreases in MABP 60 min post-hypoxia compared to baseline (p < 0.05). Overall, there was not a significant treatment effect on MABP (p > 0.05).

Treatment N Baseline 1st HX 60 min post
112 ± 5 (MABP) 112 ± 5 105 ± 5
No hypoxia 14 47.7 ± 1.2 (PaCO2) 47.7 ± 1.2 47.6 ± 1.2
267.2 ± 4.0 (PaO2) 265.9 ± 4.7 252.2 ± 8.7
112 ± 5 68 ± 4* 105 ± 4*
Intermittent hypoxia 9 45.2 ± 1.2 44.0 ± 1.7 45.9 ± 1.1
275.7 ± 6.5 38.9 ± 0.8* 262.0 ± 8.1
110 ± 4 65 ± 7* 100 ± 3*
Sustained hypoxia 14 44.4 ± 1.8 43.9 ± 0.8 44.0 ± 0.9
257.0 ± 4.9 37.9 ± 1.2* 245.4 ± 8.0
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*

Significantly different from baseline within treatment group

Hypoglossal long-term facilitation: AIH versus ASH

Representative integrated hypoglossal neurograms before, during and 60 min following AIH or ASH are presented in Figure 1. During hypoxic exposures, hypoglossal burst amplitude and frequency significantly increased in rats exposed to AIH (203 ± 31% baseline and 16 ± 3 bursts/min, respectively) and ASH hypoxia (236 ± 34% baseline and 8 ± 2 bursts/min, respectively) (Figure 2). There were no significant differences in hypoglossal burst amplitude or frequency during AIH versus ASH (Figure 2, p > 0.05 for both). Time controls showed no significant difference in hypoglossal burst amplitude or delta burst frequency at equivalent times (0 ± 3% baseline and −3 ± 2 bursts/min, respectively; Figure 2; p > 0.05).

Figure 1. Intermittent, but not sustained, hypoxia, elicits long-term facilitation (LTF) of hypoglossal (XII) motor output.

Figure 1.

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Representative integrated hypoglossal neurograms before, during, and 60 min following intermittent (top) or sustained (middle) hypoxia or no hypoxia (time control, bottom). Relative to baseline (indicated by dotted line), hypoglossal burst amplitude was increased 60 min following intermittent, but not sustained hypoxia. When hypoxia is not presented, hypoglossal motor output remains stable over time (time control). Short bar = 5 min; long bar = 25 min.

Figure 2. Hypoglossal (XII) motor output is similar during intermittent or sustained hypoxia.

Figure 2.

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Short-term response of hypoglossal burst amplitude (A) and frequency (B) during intermittent or sustained hypoxia or without hypoxia. Data are presented as mean ± SEM. * Significantly increased from baseline (p < 0.05)

Group data for hypoglossal burst amplitude 60 minutes post-hypoxia are presented in Figure 3. Hypoglossal burst amplitude was significantly increased from baseline 60 min (50 ± 20% baseline, p < 0.01) post-AIH, indicative of hypoglossal LTF (Figure 3A). In contrast, hypoglossal LTF was not observed following ASH (−6 ± 9% baseline, p > 0.05, Figure 3A). Hypoglossal burst amplitude was stable in time control rats; there were no significant changes in hypoglossal burst amplitude versus baseline at 60 minutes in this group (13 ± 9 %baseline, p > 0.05).

Figure 3. Long-term facilitation (LTF) of hypoglossal (XII) burst amplitude, but not burst frequency, is observed following intermittent, but not sustained, hypoxia.

Figure 3.

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XII burst amplitude (A) but not delta burst frequency (B) is enhanced 60 min following intermittent, but not sustained hypoxia. Data are presented as mean ± SEM. *Significantly increased from baseline (p < 0.05).

Frequency long-term facilitation

Whereas hypoglossal burst frequency increased during hypoxia (Figure 2B; p < 0.05), no significant changes were observed in hypoglossal delta burst frequency 60 min post-AIH (4 ± 3 bursts/min) or post-ASH (1 ± 2 bursts/min; both p > 0.05; Figure 3B). Time control rats did not show significant changes in hypoglossal burst frequency at an equivalent time (2 ± 1 bursts/min; p > 0.05, Figure 3B). Since there were no significant differences between groups 60 minutes post-treatment (p > 0.50), there was no evidence for frequency LTF in these experiments.

Discussion

Surprisingly, despite numerous investigations concerning phrenic LTF and pLTF pattern-sensitivity (Baker & Mitchell, 2000; Wilkerson et al., 2008; Dale-Nagle et al., 2010; Devinney et al., 2013; Devinney et al., 2015; Devinney et al., 2016), there have been no previous reports concerning the existence of pattern sensitivity in hypoglossal LTF (Baker-Herman and Strey, 2011). Using AIH and ASH protocols similar to those previously used to demonstrate pLTF pattern-sensitivity, we report that moderate AIH elicits hLTF, yet moderate ASH does not. Thus, although serotonin-dependent facilitation of intercostal motor activity lacks pattern-sensitivity in neonatal rats (Lovett-Barr et al., 2006), and hLTF differs from pLTF in certain key characteristics (Baker-Herman and Strey, 2011), the hypoglossal and phrenic motor pools exhibit similar sensitivity to the pattern of moderate hypoxia in adult rats.

We do not yet have a full understanding of mechanisms giving rise to pattern-sensitivity of hypoxia-induced respiratory motor plasticity in any motor pool. We do not even know if hLTF pattern-sensitivity occurs via the same mechanisms as pLTF pattern-sensitivity, nor if hLTF is less pattern-sensitive when severe hypoxia is applied (Devinney et al., 2016). A full understanding of mechanisms giving rise to hLTF and hLTF pattern-sensitivity will be essential if we are to fully appreciate the biological and clinical significance of this form of hypoxia-induced plasticity in motor pools innervating the upper airways.

Potential mechanisms of pattern sensitivity in hLTF

Hypoglossal and phrenic LTF exhibit many similarities and differences (Baker-Herman and Strey, 2011). Prominent differences include their responses to sex, sex hormones and ageing (Zabka et al., 2001a, 2001b, 2003, 2005, 2006; Behan et al., 2002, 2003), strain and sub-strain (Fuller et al., 2000; Mitchell et al., 2001; Fuller et al., 2001a; Baker-Herman et al., 2010), and the relative influence of alpha-adrenergic receptors in their underlying mechanisms (Neverova et al., 2007; Huxtable et al., 2014). On the other hand, both hLTF and pLTF require 5-HT2 receptor activation (Fuller et al., 2001b) and reactive oxygen species formation (MacFarlane & Mitchell, 2008a; MacFarlane et al. 2008b), suggesting fundamental similarities in their cellular/synaptic mechanisms.

Although there are no previous studies concerning mechanisms of hLTF sensitivity to the pattern of hypoxia in vivo, one study in medullary slices from juvenile rats showed that episodic, but not continuous, serotonin receptor activation elicits hLTF and increases AMPA-mediated inspiratory currents in hypoglossal motor neurons (Bocchiaro & Feldman, 2004). Similarly, hLTF is elicited by episodic alpha-adrenergic receptor activation in brainstem slice preparations (Neverova et al., 2007). These studies provide at least suggestive evidence that hypoxia-induced hLTF may also be pattern sensitive in adult rats. In contrast, phrenic and intercostal motor outputs differ in their pattern sensitivity to serotonin receptor activation in vitro, suggesting that different motor pools may vary in the extent of pattern-sensitivity to the inducing stimulus (Lovett-Barr et al., 2006).

In previous studies of pLTF pattern sensitivity, we demonstrated that inhibition of protein phosphatases with okadaic acid revealed pLTF following moderate ASH (Wilkerson et al., 2008). Since AIH-induced pLTF requires reactive oxygen species formation (MacFarlane et al., 2008a, 2008b, 2009a, 2009b), and intrathecal okadaic acid restores pLTF in rats with diminished reactive oxygen species formation (MacFarlane et al., 2008b), we suggested that pLTF pattern sensitivity arises through suppression of serine/threonine protein phosphatases that normally constrain pLTF expression via increased reactive species formation that is characteristic of AIH and not ASH (MacFarlane et al., 2008b; Wilkerson et al., 2007; Wilkerson et al., 2008). The relevant reactive oxygen species formation most arises from increased NADPH oxidase activity elicited by episodic serotonin spinal receptor activation (MacFarlane et al., 2009a). Since this form phrenic motor facilitation requires episodic serotonin receptor activation, and is not activated by a single serotonin injection of the same cumulative dose, we suggested that pLTF pattern sensitivity arises downstream from spinal serotonin receptor activation (MacFarlane and Mitchell, 2009a). The protein tyrosine phosphatase corkscrew regulates pattern sensitivity in Drosophila long-term memory induction (Pagani et al., 2009), suggesting that phosphatases play a role in multiple forms of pattern-sensitive neuroplasticity. The requirement for serotonin-dependent reactive oxygen species formation, and suppression of okadaic acid sensitive protein phosphatases in hLTF has not been investigated.

Additional insights concerning mechanisms of pLTF pattern sensitivity were inspired by the realization that multiple competing cellular mechanisms are capable of giving rise to long-lasting phrenic motor facilitation (Dale-Nagle et al., 2010; Devinney et al., 2013). The “Q pathway” to phrenic motor facilitation is initiated by Gq protein coupled metabotropic receptors such as serotonin type 2 receptors, and gives rise to pLTF following moderate AIH (Dale-Nagle et al., 2010). In contrast, the “S pathway” to phrenic motor facilitation is initiated by Gs protein coupled metabotropic receptors such as adenosine 2A receptors (Dale-Nagle et al., 2010). These pathways interact via cross talk inhibition, suggesting that there is a point where they are equal and opposing, cancelling the expression of phrenic motor facilitation (Devinney et al., 2013). Whereas the serotonin-dependent Q pathway predominates with moderate AIH, we proposed that serotonin and adenosine receptor activation are more balanced with ASH, effectively cancelling pLTF expression (Devinney et al., 2016). Selective inhibition of spinal serotonin or adenosine 2A receptors disrupts this balance, revealing pLTF following moderate ASH (Devinney et al., 2016). Similar studies exploring hLTF pattern-sensitivity have not been done.

Significance of pattern sensitivity in respiratory neuroplasticity

The importance of patterned stimulation in evoking plasticity is described in many different models of plasticity, yet the mechanism remains unknown. For example, intermediate-term memory formation and synaptic facilitation in the sea slug Aplysia (Mauelshagen et al., 1998; Sutton et al., 2002), habituation in the crab (Freudenthal et al., 1998), olfactory memory formation in fruit flies (Isabel et al., 2004), and hippocampal long-term potentiation in rodents (Kauer, 1999; Nguyen et al., 2000; Scharf et al., 2002) all exhibit apparent pattern sensitivity to the induction protocol. However, there are certain instances of pattern-insensitive plasticity. In the whole brainstem-spinal cord preparation, long term facilitation of thoracic intercostal motor output is elicited by a continuous infusion of 5-HT (Lovett-Barr et al., 2006). Another example of pattern insensitive respiratory plasticity is ventilatory acclimatization to chronic hypoxia, such as occurs during exposure to high altitude (Dwinell & Powell, 1999). Thus, by describing pattern sensitivity in respiratory neuroplasticity, we may yield insights as to why pattern sensitivity exists in some motor pools, and mechanisms giving rise to that pattern sensitivity. Understanding pattern-sensitive aspects of respiratory neuroplasiticity will also guide its optimal utilization in strategies aiming to increase respiratory motor output through induction of plasticity.

Significance of hLTF

The physiological significance of any form of respiratory plasticity is not completely understood (Mitchell et al., 2001; Mahamed and Mitchell, 2007; Fields and Mitchell, 2015). However, hLTF represents one potential mechanism to increase upper airway tone, thereby preserving upper airway patency and possibly minimizing obstructive apneas due to upper airway collapse in normal individuals or those with sleep-disordered breathing (Mitchell et al., 2001; Fuller, 2005; Mitchell, 2007; Mahamed and Mitchell, 2007; Baker-Herman and Strey, 2011). Furthermore hLTF might represent mechanisms enabling long-term adaptations of hypoglossal motor output during normal ageing (Zabka et al., 2005), or central nervous system injury or disease (Mitchell et al., 2001; Mitchell, 2007). Understanding mechanisms of hypoglossal motor facilitation will aid attempts to utilize hLTF to increase upper airway tone for therapeutic advantage. Elucidating mechanisms of hLTF pattern sensitivity will increase basic understanding of pattern sensitivity in neuroplasticity, and could guide strategies that utilize plasticity to treat disease and/or injury.

In humans, upper airway collapse increases from evening to morning, independent of sleep stage (Mateika et al., 2015, Sforza et al., 1998, Charbonneau et al., 1994). Further, intermittent hypoxia in humans elicits a distinct form of respiratory plasticity known as progressive augmentation (Powell et al., 1998), which increases the number of flow limiting breathing events (Yokhana et al., 2012, Mateika and Syed, 2013; Mateika and Narwani, 2009). Consequently, LTF of upper airway muscle activity may help offset otherwise detrimental forms of respiratory plasticity (El-Chami et al., 2017, Mateika and Komnenov, 2017).

Highlights:

  • Long-term facilitation of hypoglossal motor output induced by moderate hypoxia is pattern-sensitive

  • Intermittent, but not sustained, moderate hypoxia, elicits hypoglossal long-term facilitation

  • Long-term facilitation of hypoglossal motor output results from enhanced hypoglossal burst amplitude versus frequency

Acknowledgements:

This work was supported by the National Institutes of Health (Grants HL080209 and HL111598, GSM).

Support provided by NIH Grants HL080209 and HL111598 (GSM).

Footnotes

Conflicts of Interest: The authors declare no competing financial interests.

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