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Review
. 2018 Mar:149:42-59.
doi: 10.1016/j.bcp.2018.01.017. Epub 2018 Jan 9.

Regulation of vascular tone homeostasis by NO and H2S: Implications in hypertension

Sevda Gheibi  1 , Sajad Jeddi  2 , Khosrow Kashfi  3 , Asghar Ghasemi  4
Affiliations
Review

Regulation of vascular tone homeostasis by NO and H2S: Implications in hypertension

Sevda Gheibi et al. Biochem Pharmacol. 2018 Mar.

Abstract

Nitric oxide (NO) and hydrogen sulfide (H2S) are two gasotransmitters that are produced in the vasculature and contribute to the regulation of vascular tone. NO and H2S are synthesized in both vascular smooth muscle and endothelial cells; NO functions primarily through the sGC/cGMP pathway, and H2S mainly through activation of the ATP-dependent potassium channels; both leading to relaxation of vascular smooth muscle cells. A deficit in the NO/H2S homeostasis is involved in the pathogenesis of various cardiovascular diseases, especially hypertension. It is now becoming increasingly clear that there are important interactions between NO and H2S and that have a profound impact on vascular tone and this may provide insights into the new therapeutic interventions. The aim of this review is to provide a better understanding of individual and interactive roles of NO and H2S in vascular biology. Overall, available data indicate that both NO and H2S contribute to vascular (patho)physiology and in regulating blood pressure. In addition, boosting NO and H2S using various dietary sources or donors could be a hopeful therapeutic strategy in the management of hypertension.

Keywords: Cell signaling; Hydrogen sulfide; Hypertension; Nitric oxide; Protein modification; Vascular tone.

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Conflict of interest statement

Conflicts of interest

None

Figures

Figure 1
Figure 1. Hydrogen sulfide and nitric oxide biosynthetic pathways in vessels
Hydrogen sulfide (H2S) and nitric oxide (NO) are generated by enzymatic and non-enzymatic pathways. Non-enzymatic production of H2S in the vessels, shown in the boxes, has not yet been fully understood. NO is produced by nitrate/nitrite pathway which can be enzymatic or non-enzymatic. In endothelial cells, vasoconstrictor agonists through phospholipase Cβ (PLCβ)/ inositol-3-phosphate (IP3) and diacylglycerol (DAG) pathways increase [Ca2+]i and cause formation of calcium-calmodulin (CaM). CaM stimulates both endothelial NO synthase (eNOS) and cystathionine γ-lyase (CSE) that generate NO and H2S, respectively. H2S can increase eNOS activity and therefore NO production directly or through Akt activation. NO increases CSE activity and expression and enhances H2S production. H2S is also produced in periadventitial adipose tissue (PAT) by CSE and cystathionine-beta-synthase (CBS). Cys, Cysteine; HCY, homocysteine; NH3, ammonia; 3-MP, 3-mercaptopyruvate; 3-MST, 3-mercaptopyruvate sulfuretransferase; CAT, cysteine aminotransferase; α-KG, α-ketoglutarate.
Figure 2
Figure 2. Mechanisms of hydrogen sulfide-induced vasorelaxation
In vascular smooth muscle (VSM) cell, H2S causes hyperpolarization, which closes voltage-dependent Ca2+-channels (VDCC) and therefore relaxes smooth muscle from different pathways: (1) activation of KATP channels, (2) protein kinase C (PKC)/protein kinase A (PKA)-dependent activation of chloride/bicarbonate exchanger (CBE), (3) activation of big conductance Ca2+-activated K+ (BKCa) channels and (4) activation of voltage-dependent K+ (Kv) channels. In addition, H2S inhibits Ca2+ release from inositol triphosphate receptors (IP3) channels (5) and activates Ca2+ sparks (6). Diffused H2S from periadventitial adipose tissue (PAT) activates KATP, BKCa, and Kv channels on VSM and causes hyperpolarization (7). In endothelium, H2S causes hyperpolarization through activation of SKCa, IKCa, and BKCa channels and also KATP channels (8); hyperpolarization transfer from endothelial to VSM cells via myoepithelial gap junctions (MEGJ) (9). In addition, H2S increases intracellular Ca2+ concentration by acting on phospholipase Cβ (PLCβ) (10), and transient receptor potential (TRP) channels (11), which favor reverse mode of Na+-Ca2+ exchanger (NCX) (12), and activates cytochrome P450 epoxygenase (Cyp2C) (13) and production of epoxyeicosatrienoic acid (EET) (14); EET diffuse to VSM and activates Ca2+ sparks (15), which leads to relaxation. ER, endoplasmic reticulum; SR, sarcoplasmic reticulum; DAG, diacylglycerol; RyRs, ryanodine receptors.
Figure 3
Figure 3. Interaction between hydrogen sulfide and nitric oxide signaling pathways in vessels
Vasoconstrictor agonists through Gq/11/phospholipase Cβ (PLCβ) increases [Ca2+]i and causes contraction through calcium-calmodulin (CaM)/myosin light-chain kinase (MLCK) pathway (1). Diacylglycerol (DAG) activates protein kinase C (PKC), which phosphorylates MLCK and Rho kinase (2). Vasoconstrictor receptors are also coupled to G12/13, which activates Rho guanine nucleotide exchange factors (GEFs) and then Rho-kinase, which inhibits myosin light-chain phosphatase (MLCP) (3). NO through sGC/cGMP/PKG pathway (4) inhibits transient receptor potential type C (TRPC) channels, voltage-dependent calcium channels (VDCC), and inositol-3-phosphate (IP3) receptor (IP3R), as well as activates inward-rectifier K+ channels (Kir), big conductance Ca2+ activated K+ channels (BKCa), voltage-dependent K+ channels (Kv), ATP-sensitive K+ channel (KATP), and ryanodine receptors (RyR) in vascular smooth muscle (VSM) cells. PKG inhibits Gq/11 and PLCβ (5) as well as activates sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) (6) and decreases [Ca2+]i and therefore causes VSM relaxation. NO reacts with superoxide anion (O2-) to produce ONOO−, which activates SERCA (7). H2S inhibits phosphodiesterase (PDE) and activates the cGMP–PKG pathway (8). In addition, H2S activates Kir, BKCa, Kv, KATP, and RyR independent of cGMP–PKG pathway (9). PIP2, phosphatidylinositol 4,5-bisphosphate; sGC, soluble guanylyl cyclase.
Figure 4
Figure 4. Intermediates produced from reaction between hydrogen sulfide and nitric oxide and their vasoregulatory effects
HSSH, hydrogen persulfide.
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