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Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Growth and Remodeling

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ABSTRACT

Ischemic vascular remodeling occurs in response to stenosis or arterial occlusion leading to a change in blood flow and tissue perfusion. Altered blood flow elicits a cascade of molecular and cellular physiological responses leading to vascular remodeling of the macro‐ and micro‐circulation. Although cellular mechanisms of vascular remodeling such as arteriogenesis and angiogenesis have been studied, therapeutic approaches in these areas have had limited success due to the complexity and heterogeneous constellation of molecular signaling events regulating these processes. Understanding central molecular players of vascular remodeling should lead to a deeper understanding of this response and aid in the development of novel therapeutic strategies. Hydrogen sulfide (H2S) and nitric oxide (NO) are gaseous signaling molecules that are critically involved in regulating fundamental biochemical and molecular responses necessary for vascular growth and remodeling. This review examines how NO and H2S regulate pathophysiological mechanisms of angiogenesis and arteriogenesis, along with important chemical and experimental considerations revealed thus far. The importance of NO and H2S bioavailability, their synthesis enzymes and cofactors, and genetic variations associated with cardiovascular risk factors suggest that they serve as pivotal regulators of vascular remodeling responses. © 2019 American Physiological Society. Compr Physiol 9:1213‐1247, 2019.

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Figure 1. Figure 1. Vascular remodeling due to arteriogenesis or angiogenesis: remodeling of macro‐ and microvasculature occurs through arteriogenesis and angiogenesis, respectively. (A) In the absence of occlusion, blood flow across two arterial branches is minimal resulting in equivalent pressure (P1 = P2). Upon arterial occlusion of one branch, fluid shear stress due to altered blood flow causes differential pressure (P1 > P2), resulting in increased luminal diameter (D1 < D2) and vascular wall thickness (T1 < T2). (B) Angiogenesis is a multistep process involving endothelial cell activation and extracellular matrix degradation followed by tip cell sprouting and progressive vessel stalk elongation. Further structural support and vessel stabilization occur by pericyte recruitment.
Figure 2. Figure 2. CSE modulates flow induced vascular remodeling: CSE expression and sulfane sulfur production are enhanced by disturbed flow in conduit vessels. The enhanced CSE expression causes increased macrophage recruitment in these areas leading to flow induced vascular remodelling. In case of CSE knockout animals, they showed reduced sulfane sulfur levels following partial carotid artery ligation, defective inward remodeling, and a dilated vascular phenotype. The dilated phenotype is due to elevated NO bioavailability in CSE knockout carotid arteries.
Figure 3. Figure 3. The nitric oxide synthesis pathway: under normal oxygen parameters (normoxia), in the presence of NAPDH and cofactors such as BH4, FMN, FAD, and eNOS catalyze the conversion of L‐arginine to L‐citrulline and NO. Further, one electron oxidation of NO catalyzed by ceruloplasmin in plasma and cytochrome c oxidase in tissues yields nitrite, further with relatively faster two‐electron oxidation yielding nitrate by heme proteins in blood and tissues. In the absence of oxygen (hypoxia), nitrite is reduced by reductases, including xanthine oxidase, deoxyhemoglobin, deoxymyoglobin to produce NO. Further, oxidative stress leads to BH4 oxidation and eNOS uncoupling leading to superoxide production.
Figure 4. Figure 4. A schematic diagram of nitrate, nitrite, and nitric oxide (NO) pathway from exogenous (dietary) sources: dietary nitrate taken () is absorbed systemically () and is concentrated 10‐fold in the salivary gland and enters the enterosalivary circulatory system where it is converted to nitrite by bacterial nitrite reductases on the dorsum of the tongue (). When nitrite reaches the lumen of the stomach, acidic gastric juice converts nitrite to nitrosating species that can further react with ascorbic acid in gastric juice to yield NO (). It can also reenter the circulation as nitrite and be reduced to NO by xanthine oxidase (XO) and aldehyde oxidase (AO) (). Nitrite in the arterial circulation may also be reduced to nitric oxide due to hemoglobin deoxygenation causing vasodilation ().
Figure 5. Figure 5. Principal reactions of nitric oxide in tissues: nitric oxide produced in the endothelium diffuses into vascular smooth muscle cells and activates soluble guanylate cyclase, which in turn initiates the production of the messenger cGMP (cyclic guanosine monophosphate). cGMP relaxes smooth muscle cells in the vessel walls leading to vasodilation. NO can also diffuse into red blood cells and react with oxyhemoglobin to form methemoglobin and nitrate.
Figure 6. Figure 6. Schematic representation of H2S generating reactions: this figure is a schematic representation of H2S generating reactions of CBS, CSE, and MPST. CBS and CSE, catalyze elimination/addition reactions at the β‐ and γ‐positions of sulfur‐containing amino acids, respectively.
Figure 7. Figure 7. Regulation of H2S production: L‐Cysteine can be converted to H2S via cystathionine β‐synthase (CBS) or cystathionine γ‐lyase (CSE), both of which require pyroxidal‐5‐phosphate for their activity. L‐Cysteine can also be converted to 3‐mercaptopyruvate via cysteine aminotransferase (CAT), which can, in turn, be metabolized by 3‐mercaptopyruvate sulfurtransferase (MPST) to generate H2S. Further H2S is oxidized by sulfide quinone oxidoreductase (SQR) in mitochondria to produce SQR‐persulfide. Sulfur dioxygenase oxidizes persulfide to sulfite (H2SO3), which is metabolized by rhodanese to produce thiosulfate (H2S2O3). The balance between H2S synthesis and catabolism determines its cellular concentration.
Figure 8. Figure 8. Reactivity of H2S and H2Sn: H2S is generated by CSE, CBS, and MPST. H2S can undergo one‐electron oxidation or two‐electron oxidation to form HSOH or form S•‐, respectively. Both of them can be oxidized to persulfide. According to the bimolecular rate constants for reaction of H2S oxidation, H2S is oxidized slower by H2O2 than that of superoxide. MPST receive sulfur from 3MP to generate MPST polysulfide chain, which can be reduced by thioredoxin (Trx) to release H2Sn, such as H2S, H2S2, H2S3, etc. Once H2S is produced, it can be oxidized to hydrogen thioperoxide (HSOH), sulfurous acid (H2SO3), thiosulfuric acid (H2S2O3), sulfuric acid (H2SO4), etc. In addition, it also reacts with intracellular thiols (cysteine, glutathione, and protein cysteine residue) to form their persulfide forms.
Figure 9. Figure 9. A schematic representation of H2S‐mediated ischemic vascular signaling: (A and B) Plasma and tissue sulfide and NOx levels in WT mice followed by femoral artery ligation. (C) Ischemia leads to increased CSE expression, activity, and H2S generation. Further H2S increases VEGF production and phosphorylates eNOS leading to elevated NO bioavailability. H2S‐dependent stimulation of NO activate the cGMP/PKG pathway by acting on sGC and regulates angiogenesis, arteriogenesis through cytokines and monocyte recruitment. H2S also leads to XO‐mediated nitrite reduction to NO, under ischemic/hypoxic condition. Further, CSE‐derived H2S causes vasodilation by activating ion channels and hyperpolarizing the vascular wall.
Figure 10. Figure 10. Regulation of endothelial permeability by CSE‐derived sulfur species: schematic overview showing the CSE‐derived polysulfides increased endothelial solute permeability associated with disruption of endothelial junction proteins claudin 5 and VE‐cadherin, along with enhanced actin stress fiber formation.
Figure 11. Figure 11. A schematic diagram of the interaction of NO and H2S: NO and H2S are directly involved in regulation of heme function. The reaction of NO and sulfide radical can form nitrosothiol (RSNO), which can also be produced from the reaction of dinitrogen trioxide (N2O3) and thiol. RSNO is reactive nitrogen species, and further reacts with glutathione (GSH) or thiol, resulting in the production of glutathionylated thiol (RSSG), disulfide bonds (RS‐SR), or sulfhydrated thiol (PSSH, PS‐(S) n‐SH), respectively. NO and H2S also can be oxidized to form dinitrogen trioxide (N2O3), nitrogen dioxide (NO2), nitrite (NO2), peroxynitrite (ONOO), nitroxyl (HNO), sulfenic acid (R‐SOH), sulfinic acid (R‐SO2H), sulfonic acid (R‐SO3H), sulfite (SO32−), sulfate (SO42−), respectively. R‐SOH can be directly reduced to free thiol by Trx, or further oxidized to generate R‐SO2H or R‐SO3H. HNO can quickly dimerize to hyponitrous acid (H2N2O2), which is then dehydrated to nitrous oxide (N2O). HNO can also generate hydroxylamine ammonia (NH2OH).


Figure 1. Vascular remodeling due to arteriogenesis or angiogenesis: remodeling of macro‐ and microvasculature occurs through arteriogenesis and angiogenesis, respectively. (A) In the absence of occlusion, blood flow across two arterial branches is minimal resulting in equivalent pressure (P1 = P2). Upon arterial occlusion of one branch, fluid shear stress due to altered blood flow causes differential pressure (P1 > P2), resulting in increased luminal diameter (D1 < D2) and vascular wall thickness (T1 < T2). (B) Angiogenesis is a multistep process involving endothelial cell activation and extracellular matrix degradation followed by tip cell sprouting and progressive vessel stalk elongation. Further structural support and vessel stabilization occur by pericyte recruitment.


Figure 2. CSE modulates flow induced vascular remodeling: CSE expression and sulfane sulfur production are enhanced by disturbed flow in conduit vessels. The enhanced CSE expression causes increased macrophage recruitment in these areas leading to flow induced vascular remodelling. In case of CSE knockout animals, they showed reduced sulfane sulfur levels following partial carotid artery ligation, defective inward remodeling, and a dilated vascular phenotype. The dilated phenotype is due to elevated NO bioavailability in CSE knockout carotid arteries.


Figure 3. The nitric oxide synthesis pathway: under normal oxygen parameters (normoxia), in the presence of NAPDH and cofactors such as BH4, FMN, FAD, and eNOS catalyze the conversion of L‐arginine to L‐citrulline and NO. Further, one electron oxidation of NO catalyzed by ceruloplasmin in plasma and cytochrome c oxidase in tissues yields nitrite, further with relatively faster two‐electron oxidation yielding nitrate by heme proteins in blood and tissues. In the absence of oxygen (hypoxia), nitrite is reduced by reductases, including xanthine oxidase, deoxyhemoglobin, deoxymyoglobin to produce NO. Further, oxidative stress leads to BH4 oxidation and eNOS uncoupling leading to superoxide production.


Figure 4. A schematic diagram of nitrate, nitrite, and nitric oxide (NO) pathway from exogenous (dietary) sources: dietary nitrate taken () is absorbed systemically () and is concentrated 10‐fold in the salivary gland and enters the enterosalivary circulatory system where it is converted to nitrite by bacterial nitrite reductases on the dorsum of the tongue (). When nitrite reaches the lumen of the stomach, acidic gastric juice converts nitrite to nitrosating species that can further react with ascorbic acid in gastric juice to yield NO (). It can also reenter the circulation as nitrite and be reduced to NO by xanthine oxidase (XO) and aldehyde oxidase (AO) (). Nitrite in the arterial circulation may also be reduced to nitric oxide due to hemoglobin deoxygenation causing vasodilation ().


Figure 5. Principal reactions of nitric oxide in tissues: nitric oxide produced in the endothelium diffuses into vascular smooth muscle cells and activates soluble guanylate cyclase, which in turn initiates the production of the messenger cGMP (cyclic guanosine monophosphate). cGMP relaxes smooth muscle cells in the vessel walls leading to vasodilation. NO can also diffuse into red blood cells and react with oxyhemoglobin to form methemoglobin and nitrate.


Figure 6. Schematic representation of H2S generating reactions: this figure is a schematic representation of H2S generating reactions of CBS, CSE, and MPST. CBS and CSE, catalyze elimination/addition reactions at the β‐ and γ‐positions of sulfur‐containing amino acids, respectively.


Figure 7. Regulation of H2S production: L‐Cysteine can be converted to H2S via cystathionine β‐synthase (CBS) or cystathionine γ‐lyase (CSE), both of which require pyroxidal‐5‐phosphate for their activity. L‐Cysteine can also be converted to 3‐mercaptopyruvate via cysteine aminotransferase (CAT), which can, in turn, be metabolized by 3‐mercaptopyruvate sulfurtransferase (MPST) to generate H2S. Further H2S is oxidized by sulfide quinone oxidoreductase (SQR) in mitochondria to produce SQR‐persulfide. Sulfur dioxygenase oxidizes persulfide to sulfite (H2SO3), which is metabolized by rhodanese to produce thiosulfate (H2S2O3). The balance between H2S synthesis and catabolism determines its cellular concentration.


Figure 8. Reactivity of H2S and H2Sn: H2S is generated by CSE, CBS, and MPST. H2S can undergo one‐electron oxidation or two‐electron oxidation to form HSOH or form S•‐, respectively. Both of them can be oxidized to persulfide. According to the bimolecular rate constants for reaction of H2S oxidation, H2S is oxidized slower by H2O2 than that of superoxide. MPST receive sulfur from 3MP to generate MPST polysulfide chain, which can be reduced by thioredoxin (Trx) to release H2Sn, such as H2S, H2S2, H2S3, etc. Once H2S is produced, it can be oxidized to hydrogen thioperoxide (HSOH), sulfurous acid (H2SO3), thiosulfuric acid (H2S2O3), sulfuric acid (H2SO4), etc. In addition, it also reacts with intracellular thiols (cysteine, glutathione, and protein cysteine residue) to form their persulfide forms.


Figure 9. A schematic representation of H2S‐mediated ischemic vascular signaling: (A and B) Plasma and tissue sulfide and NOx levels in WT mice followed by femoral artery ligation. (C) Ischemia leads to increased CSE expression, activity, and H2S generation. Further H2S increases VEGF production and phosphorylates eNOS leading to elevated NO bioavailability. H2S‐dependent stimulation of NO activate the cGMP/PKG pathway by acting on sGC and regulates angiogenesis, arteriogenesis through cytokines and monocyte recruitment. H2S also leads to XO‐mediated nitrite reduction to NO, under ischemic/hypoxic condition. Further, CSE‐derived H2S causes vasodilation by activating ion channels and hyperpolarizing the vascular wall.


Figure 10. Regulation of endothelial permeability by CSE‐derived sulfur species: schematic overview showing the CSE‐derived polysulfides increased endothelial solute permeability associated with disruption of endothelial junction proteins claudin 5 and VE‐cadherin, along with enhanced actin stress fiber formation.


Figure 11. A schematic diagram of the interaction of NO and H2S: NO and H2S are directly involved in regulation of heme function. The reaction of NO and sulfide radical can form nitrosothiol (RSNO), which can also be produced from the reaction of dinitrogen trioxide (N2O3) and thiol. RSNO is reactive nitrogen species, and further reacts with glutathione (GSH) or thiol, resulting in the production of glutathionylated thiol (RSSG), disulfide bonds (RS‐SR), or sulfhydrated thiol (PSSH, PS‐(S) n‐SH), respectively. NO and H2S also can be oxidized to form dinitrogen trioxide (N2O3), nitrogen dioxide (NO2), nitrite (NO2), peroxynitrite (ONOO), nitroxyl (HNO), sulfenic acid (R‐SOH), sulfinic acid (R‐SO2H), sulfonic acid (R‐SO3H), sulfite (SO32−), sulfate (SO42−), respectively. R‐SOH can be directly reduced to free thiol by Trx, or further oxidized to generate R‐SO2H or R‐SO3H. HNO can quickly dimerize to hyponitrous acid (H2N2O2), which is then dehydrated to nitrous oxide (N2O). HNO can also generate hydroxylamine ammonia (NH2OH).
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Teaching Material

S. Rajendran, X. Shen, J. Glawe, G. K. Kolluru, C. G. Kevil. Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Growth and Remodeling. Compr Physiol 9: 2019, 1211-1245.

Didactic Synopsis

Major Teaching Points:

  • A robust and functional vascular network is a fundamental process in development, growth, and tissue maintenance.
  • Based on the mechanism, occurrence and result, vascular growth can be distinguished principally as three types
    • Vasculogenesis - de novo formation of a primitive vascular network
    • Angiogenesis - new capillaries form from pre-existing blood vessels
    • Arteriogenesis - mature arteries form from interconnecting arterioles after an arterial occlusion.
  • Ischemic vascular remodeling occurs as a result of stenosis or arterial occlusion.
  • Nitric oxide and Hydrogen sulfide are known to be is essential for ischemic vascular remodeling.
  • The pathophysiological events of angiogenesis and arteriogenesis regulated by NO and H2S involve multiple cellular responses suggesting central roles in mediating vascular remodeling.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1 Teaching points: A: Normal flow through conduit arteries (on the left). Following arterial occlusion, vessels adapt to flow in order to withstand the shear stress to which they are subjected (P1>P2). As a result, blood flows through collateral anastomoses, altering the lumen diameter (D1<D2) of arteries and vascular wall thickness (T1 < T2) (on the right). (B) Angiogenesis is a multi-step process involving endothelial cell activation and extracellular matrix degradation followed by tip cell sprouting and progressive vessel stalk elongation. Further structural support and vessel stabilization occur by pericytes recruitment.

Figure 2 Teaching points: Blood flow critically regulates vascular homeostasis and function. During unidirectional laminar flow, endothelial cells exhibit a quiescent phenotype associated with NO bioavailability, enhanced eNOS activity, reduced oxidant stress, low endothelial turnover, enhanced barrier function, and limited proinflammatory gene expression. In contrast, in regions of disturbed flow are atheroprone with reduced NO production, increased oxidative stress and increased proinflammatory gene expression. Following partial carotid artery ligation, the disturbed flow regions show increased CSE expression and sulfane sulfur content, which is blunted by genetic CSE deficiency. CSE knockout mice exhibit a dilated phenotype and reduced medial thickening, which is due to elevated NO production in the carotid arteries.

Figure 3 Teaching points: NO is produced primarily by NOS. NOS has three different isoforms namely neuronal NOS (nNOS), inducible NOS (iNOS), endothelial NOS (eNOS). Under normoxic conditions, eNOS predominantly present in endothelial cells and other NOS produce NO by catalyzing the oxidation of L-arginine to L-citrulline in the presence of various cofactors. Further, one electron oxidation of NO catalyzed by ceruloplasmin in plasma and cytochrome c oxidase in tissues yields nitrite, further with relatively faster two-electron oxidation yielding nitrate by heme proteins in blood and tissues. In the absence of oxygen (hypoxia), nitrite is reduced by reductases, including xanthine oxidase, deoxyhemoglobin, deoxymyoglobin to produce NO. Further oxidative stress leads to BH4 oxidation and eNOS uncoupling leading to superoxide production.

Figure 4 Teaching points: Nitrate is the predominant nitric oxide oxidation product in the circulation. (1) Ingestion of dietary nitrate and is absorbed from the stomach and small intestine (2); concentration of nitrate in the salivary gland; (3) oral commensal bacteria containing bacterial nitrate reductases reduce nitrate to nitrite; (4) when nitrite reaches the lumen of the stomach, it meets the acidic gastric juice that converts nitrite to nitrosating species, which further reacts with the ascorbic acid in gastric juice to yield NO. It can also re-enter the circulation as nitrite and be reduced to NO by xanthine oxidase (XO) and aldehyde oxidase (AO); (5) nitrite in the arterial circulation gets reduced to nitric oxide due to hemoglobin deoxygenation facilitating vasodilation.

Figure 5 Teaching points: In the endothelium NOS catalyzes the conversion of L-Arginine to L-Citrulline producing NO. Nitric oxide produced in the endothelium activates soluble guanylate cyclase, which in turn initiates the production of the messenger cGMP (cyclic guanosine monophosphate). cGMP causes the smooth muscle cells in the vessel walls to vasodilate. NO further diffuse into blood, and reacts with oxyhemoglobin (HbO2) to form methemoglobin and nitrate.

Figure 6 Teaching points: This figure is a schematic representation of H2S generating reactions of CBS, CSE and MPST. CBS and CSE, catalyze elimination/addition reactions at the β- and γ-positions of sulfur-containing amino acids, respectively.

Figure 7 Teaching points: CBS, CSE and MPST are the three major enzymes involved in H2S synthesis. CBS and CSE are components of transulfuration pathway. This pathway is responsible for the conversion of L-Cysteine to H2S via cystathionine β-synthase (CBS) or cystathionine γ-lyase (CSE), both of which require pyroxidal-5-phosphate (P5P) for their activity. MPST is a part of cysteine catabolism pathway using 3-MP as substrate. L-Cysteine can also be converted to 3-mercaptopyruvate via cysteine aminotransferase (CAT), which can, in turn, be metabolized by 3-mercaptopyruvate sulfurtransferase (MPST) to generate H2S. Further H2S is oxidized by sulfide quinone oxidoreductase (SQR) in mitochondria to produce SQR-persulfide. Sulfur dioxygenase oxidizes persulfide to sulfite (H2SO3), which is metabolized by rhodanese to produce thiosulfate (H2S2O3). The balance between H2S synthesis and catabolism determines its cellular concentration.

Figure 8 Teaching points: H2S is generated by CSE, CBS, and MPST. H2S can undergo one-electron oxidation or two-electron oxidation to form HSOH or form S•, respectively. Both of them can be oxidized to persulfide. According to the bimolecular rate constants for reaction of H2S oxidation, H2S is oxidized slower by H2O2 than that of superoxide. MPST receive sulfur from MP to generate MPST polysulfide chain which can be reduced by thioredoxin (Trx) to release H2Sn, such as H2S, H2S2, H2S3, etc. Once H2S is produced, it can be oxidized to hydrogen thioperoxide (HSOH), sulfurous acid (H2SO3), thiosulfuric acid (H2S2O3) and sulfuric acid (H2SO4) etc. In addition, it also reacts with intracellular thiols (cysteine, glutathione and protein cysteine residue) to form their persulfide forms.

Figure 9 Teaching points: (A & B) Plasma and tissue sulfide and NOx levels in WT mice followed by femoral artery ligation. (C) Ischemia leads to increased CSE expression, activity and H2S generation. Further H2S increases VEGF production and phosphorylates eNOS leading to elevated NO bioavailability. H2S dependent stimulation of NO activate the cGMP/PKG pathway by acting on sGC and regulates angiogenesis, arteriogenesis through cytokines and monocyte recruitment. H2S also leads to XO mediated nitrite reduction to NO, under ischemic/hypoxic condition. Further, CSE-derived H2S causes vasodilation by activating ion channels and hyperpolarizing the vascular wall.

Figure 10 Teaching points: This figure illustrates that CSE derived polysulfides increased endothelial solute permeability associated with disruption of endothelial junction proteins claudin 5 and VE-cadherin, along with enhanced actin stress fiber formation in the endothelium.

Figure 11 Teaching points: NO and H2S are directly involved in regulation of heme function. The reaction of NO and sulfide radical can form nitrosothiol (RSNO), which can also be produced from the reaction of dinitrogen trioxide (N2O3) and thiol. RSNO is reactive nitrogen species, and further react with glutathione (GSH) or thiol, resulting in the production of glutathionylated thiol (RSSG), disulfide bonds (RS-SR), or sulfhydrated thiol (PSSH, PS-(S) n-SH), respectively. NO and H2S also can be oxidized to form dinitrogen trioxide (N2O3), nitrogen dioxide (NO2), nitrite (NO2), peroxynitrite (ONOO), nitroxyl (HNO), sulfenic acid (R-SOH), sulfinic acid (R-SO2H), sulfonic acid (R-SO3H), sulfite (SO32−), sulfate (SO42−), respectively. R-SOH can be directly reduced to free thiol by Trx, or further oxidized to generate R-SO2H or R-SO3H. HNO can quickly dimerize to hyponitrous acid (H2N2O2), which is then dehydrated to nitrous oxide (N2O). HNO can also generate hydroxylamine ammonia (NH2OH).

 


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Saranya Rajendran, Xinggui Shen, John Glawe, Gopi K. Kolluru, Christopher G. Kevil. Nitric Oxide and Hydrogen Sulfide Regulation of Ischemic Vascular Growth and Remodeling. Compr Physiol 2019, 9: 1213-1247. doi: 10.1002/cphy.c180026