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Review
. 2019 Jun 12;9(3):1213-1247.
doi: 10.1002/cphy.c180026.

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

Saranya Rajendran  1 , Xinggui Shen  1 , John Glawe  1 , Gopi K Kolluru  1 , Christopher G Kevil  1   2   3
Affiliations
Review

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

Saranya Rajendran et al. Compr Physiol. .

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 (H2 S) 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 H2 S regulate pathophysiological mechanisms of angiogenesis and arteriogenesis, along with important chemical and experimental considerations revealed thus far. The importance of NO and H2 S 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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Figures

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 (1) is absorbed systemically (2) 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 (3). 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 (4). It can also reenter the circulation as nitrite and be reduced to NO by xanthine oxidase (XO) and aldehyde oxidase (AO) (4). Nitrite in the arterial circulation may also be reduced to nitric oxide due to hemoglobin deoxygenation causing vasodilation (5).
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).
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References

    1. Abe K, Kimura H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16: 1066–1071, 1996. - PMC - PubMed
    1. Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAllister R, Vallance P. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolized by dimethylarginine dimethylaminohydrolase. Arterioscler Thromb Vasc Biol 23: 1455–1459, 2003. - PubMed
    1. Aicher A, Heeschen C, Mildner-Rihm C, Urbich C, Ihling C, Technau-Ihling K, Zeiher AM, Dimmeler S. Essential role of endothelial nitric oxide synthase for mobilization of stem and progenitor cells. Nat Med 9: 1370–1376, 2003. - PubMed
    1. Aras O, Hanson NQ, Yang F, Tsai MY. Influence of 699C→T and 1080C→T polymorphisms of the cystathionine beta-synthase gene on plasma homocysteine levels. Clin Genet 58: 455–459, 2000. - PubMed
    1. Arras M, Ito WD, Scholz D, Winkler B, Schaper J, Schaper W. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 101: 40–50, 1998. - PMC - PubMed

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