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Serotonin and Pulmonary Hypertension; Sex and Drugs and ROCK and Rho

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Abstract

Serotonin is often referred to as a “happy hormone” as it maintains good mood, well‐being, and happiness. It is involved in communication between nerve cells and plays a role in sleeping and digestion. However, too much serotonin can have pathogenic effects and serotonin synthesis is elevated in pulmonary artery endothelial cells from patients with pulmonary arterial hypertension (PAH). PAH is characterized by elevated pulmonary pressures, right ventricular failure, inflammation, and pulmonary vascular remodeling; serotonin has been shown to be associated with these pathologies. The rate‐limiting enzyme in the synthesis of serotonin in the periphery of the body is tryptophan hydroxylase 1 (TPH1). TPH1 expression and serotonin synthesis are elevated in pulmonary artery endothelial cells in patients with PAH. The serotonin synthesized in the pulmonary arterial endothelium can act on the adjacent pulmonary arterial smooth muscle cells (PASMCs), adventitial macrophages, and fibroblasts, in a paracrine fashion. In humans, serotonin enters PASMCs cells via the serotonin transporter (SERT) and it can cooperate with the 5‐HT1B receptor on the plasma membrane; this activates both contractile and proliferative signaling pathways. The “serotonin hypothesis of pulmonary hypertension” arose when serotonin was associated with PAH induced by diet pills such as fenfluramine, aminorex, and chlorphentermine; these act as indirect serotonergic agonists causing the release of serotonin from platelets and cells through the SERT. Here the role of serotonin in PAH is reviewed. Targeting serotonin synthesis or signaling is a promising novel alternative approach which may lead to novel therapies for PAH. © 2022 American Physiological Society. Compr Physiol 12: 1–16, 2022.

Figure 1. Figure 1. Serotonin synthesis and metabolism. Dietary tryptophan (Trp) is converted to 5‐hydroxytryptophan (5‐HTP) by tryptophan hydroxylase (TPH) 1 or 2. 5‐hydroxytryptophan (5‐HTP) is converted to serotonin (5‐HT) by aromatic l‐amino acid decarboxylase (AAAD). 5‐HT is metabolized to 5‐hydroxyindole acetic acid (5‐HIAA), a 5‐HT biosynthesis biomarker in urine and plasma, by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH). 5‐HT can also be metabolized to melatonin by N‐acetyltransferase (NAT) and 5‐hydroxyindole O‐methyltransferase (HIOMT). IDO, indoleamine 2,3‐dioxygenase; TDO, tryptophan 2,3‐dioxygenase.
Figure 2. Figure 2. Schematic illustration of serotonylation. Transglutaminase 2 (TG2, yellow) catalyzes the linkage of serotonin to distinct glutamine residues/substrate proteins (blue) to produce the serotonylated protein. 5‐HT, 5‐hydroxytryptamine (serotonin).
Figure 3. Figure 3. Schematic summary of hypoxia‐induced serotonin‐mediated pulmonary artery smooth muscle cell signaling and function. Hypoxia is associated with cellular accumulation of serotonin via SERT and TPH1; calcium via CaSR and TRPV4; and TG2 induction and activation via HIF1α and increased calcium levels, respectively. Activated TG2 mediates covalent crosslinking of serotonin with fibronectin, serotonylated fibronectin, and plays an intermediary role in the mitogenic effect of serotonin. Ca2+, Calcium; CaSR, Ca2+ sensing receptor; HIF1α, hypoxia‐inducible factor 1‐alpha; HRE, hypoxia response element; SERT, serotonin transporter; TG2, transglutaminase 2; TPH1, tryptophan hydroxylase 1; TRPPV4; transient receptor potential vanilloid‐type 4 ion channel. Dotted lines represent de novo 5‐HT synthesis via TPH1.
Figure 4. Figure 4. Study design and photomicrographs of the effect of rodatristat ethyl, ambrisentan, and tadalafil on pulmonary vessel wall thickness in male, SU5416‐hypoxia treated sprague dawley rats. PAH was induced by a single 20 mg/kg injection of Sutent® (SU5416, SUGEN) and exposure to hypoxia (11% O2) for 21 days. Rats were returned to normoxic conditions and received indicated treatments once daily for an additional 28 days. Rodatristat ethyl dose in monotherapy and combination studies (indicated as “Rodatristat” above) was 100 mg/kg/day (photomicrograph for Rodatristat ethyl alone group is from a 200 mg/kg/day treatment animal). Ambrisentan and Tadalafil were dosed at 10 mg/kg/day. Verhoeff‐Van Gieson elastin on Day 49 in cross sections of perfused, formalin‐fixed lungs was performed, and images obtained at 40× magnification. The outer and inner perimeters of the vessel walls were delineated using ImagePro software and relative vessel wall thickness was determined using the calculation: [(outer vessel wall circumference) − (inner vessel wall circumference)]/(outer vessel wall circumference). Mean pulmonary arterial blood pressure (mPAP) was measured using a Millar Mikro‐Tip® catheter. **P < 0.01,**** P < 0.0001 significance versus Sutent® (SU5416) and Hypoxia, Vehicle Group, n = 4–12 rats per group.
Figure 5. Figure 5. A summary overview of the role of serotonin in the pathogenesis of pulmonary vascular remodeling. Serotonin synthesis is increased in pulmonary arterial endothelial cells (PAECs) through increased tryptophan hydroxylase 1 (TPH1) activity. PAEC‐derived serotonin can act on underlying cells by either entering the cell through the serotonin transporter (SERT) or activating serotonin receptors. Intracellular serotonin may increase proliferative and contractile pathways such as Rho‐kinase (ROCK), reactive oxygen species (ROS), or mitogen‐activated protein kinase (MAPK), and this may be through serotonylated by transglutaminase 2, induction of nuclear growth factors such as GATA‐4 or EGR1 and increased intracellular calcium (Ca2+). Estrogen can inhibit bone morphogenetic receptor 2 (BMPR2) signaling and a decrease in BMPR2 signaling can induce a pro‐proliferative phenotype in the pulmonary arterial smooth muscle cell (PASMC). In addition, estrogen can increase the expression of TPH1, 5‐HT1B receptors, and the serotonin transporter and this may contribute further to ‐operation between the SERT and the increased proliferation of the PASMCs via the effects of serotonin. The 5‐HT1B receptor mediates contraction and proliferation in small muscular PASMCs by decreasing cAMP accumulation, stimulating increases in intracellular calcium (Ca2+). The 5‐HT2A/2B receptor may contribute to proliferative and pro‐fibrotic responses in the large capacitance pulmonary arteries and fibroblasts. There is cooperation between the SERT and 5‐HT1B receptor such that inhibition of both is required to inhibit responses to serotonin. All of these effects can lead to pulmonary vascular remodeling and thickening of the pulmonary arterial wall. Created with BioRender.com.


Figure 1. Serotonin synthesis and metabolism. Dietary tryptophan (Trp) is converted to 5‐hydroxytryptophan (5‐HTP) by tryptophan hydroxylase (TPH) 1 or 2. 5‐hydroxytryptophan (5‐HTP) is converted to serotonin (5‐HT) by aromatic l‐amino acid decarboxylase (AAAD). 5‐HT is metabolized to 5‐hydroxyindole acetic acid (5‐HIAA), a 5‐HT biosynthesis biomarker in urine and plasma, by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH). 5‐HT can also be metabolized to melatonin by N‐acetyltransferase (NAT) and 5‐hydroxyindole O‐methyltransferase (HIOMT). IDO, indoleamine 2,3‐dioxygenase; TDO, tryptophan 2,3‐dioxygenase.


Figure 2. Schematic illustration of serotonylation. Transglutaminase 2 (TG2, yellow) catalyzes the linkage of serotonin to distinct glutamine residues/substrate proteins (blue) to produce the serotonylated protein. 5‐HT, 5‐hydroxytryptamine (serotonin).


Figure 3. Schematic summary of hypoxia‐induced serotonin‐mediated pulmonary artery smooth muscle cell signaling and function. Hypoxia is associated with cellular accumulation of serotonin via SERT and TPH1; calcium via CaSR and TRPV4; and TG2 induction and activation via HIF1α and increased calcium levels, respectively. Activated TG2 mediates covalent crosslinking of serotonin with fibronectin, serotonylated fibronectin, and plays an intermediary role in the mitogenic effect of serotonin. Ca2+, Calcium; CaSR, Ca2+ sensing receptor; HIF1α, hypoxia‐inducible factor 1‐alpha; HRE, hypoxia response element; SERT, serotonin transporter; TG2, transglutaminase 2; TPH1, tryptophan hydroxylase 1; TRPPV4; transient receptor potential vanilloid‐type 4 ion channel. Dotted lines represent de novo 5‐HT synthesis via TPH1.


Figure 4. Study design and photomicrographs of the effect of rodatristat ethyl, ambrisentan, and tadalafil on pulmonary vessel wall thickness in male, SU5416‐hypoxia treated sprague dawley rats. PAH was induced by a single 20 mg/kg injection of Sutent® (SU5416, SUGEN) and exposure to hypoxia (11% O2) for 21 days. Rats were returned to normoxic conditions and received indicated treatments once daily for an additional 28 days. Rodatristat ethyl dose in monotherapy and combination studies (indicated as “Rodatristat” above) was 100 mg/kg/day (photomicrograph for Rodatristat ethyl alone group is from a 200 mg/kg/day treatment animal). Ambrisentan and Tadalafil were dosed at 10 mg/kg/day. Verhoeff‐Van Gieson elastin on Day 49 in cross sections of perfused, formalin‐fixed lungs was performed, and images obtained at 40× magnification. The outer and inner perimeters of the vessel walls were delineated using ImagePro software and relative vessel wall thickness was determined using the calculation: [(outer vessel wall circumference) − (inner vessel wall circumference)]/(outer vessel wall circumference). Mean pulmonary arterial blood pressure (mPAP) was measured using a Millar Mikro‐Tip® catheter. **P < 0.01,**** P < 0.0001 significance versus Sutent® (SU5416) and Hypoxia, Vehicle Group, n = 4–12 rats per group.


Figure 5. A summary overview of the role of serotonin in the pathogenesis of pulmonary vascular remodeling. Serotonin synthesis is increased in pulmonary arterial endothelial cells (PAECs) through increased tryptophan hydroxylase 1 (TPH1) activity. PAEC‐derived serotonin can act on underlying cells by either entering the cell through the serotonin transporter (SERT) or activating serotonin receptors. Intracellular serotonin may increase proliferative and contractile pathways such as Rho‐kinase (ROCK), reactive oxygen species (ROS), or mitogen‐activated protein kinase (MAPK), and this may be through serotonylated by transglutaminase 2, induction of nuclear growth factors such as GATA‐4 or EGR1 and increased intracellular calcium (Ca2+). Estrogen can inhibit bone morphogenetic receptor 2 (BMPR2) signaling and a decrease in BMPR2 signaling can induce a pro‐proliferative phenotype in the pulmonary arterial smooth muscle cell (PASMC). In addition, estrogen can increase the expression of TPH1, 5‐HT1B receptors, and the serotonin transporter and this may contribute further to ‐operation between the SERT and the increased proliferation of the PASMCs via the effects of serotonin. The 5‐HT1B receptor mediates contraction and proliferation in small muscular PASMCs by decreasing cAMP accumulation, stimulating increases in intracellular calcium (Ca2+). The 5‐HT2A/2B receptor may contribute to proliferative and pro‐fibrotic responses in the large capacitance pulmonary arteries and fibroblasts. There is cooperation between the SERT and 5‐HT1B receptor such that inhibition of both is required to inhibit responses to serotonin. All of these effects can lead to pulmonary vascular remodeling and thickening of the pulmonary arterial wall. Created with BioRender.com.
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Margaret R. MacLean, Barry Fanburg, Nicolas Hill, Howard M. Lazarus, Thomas F. Pack, Michelle Palacios, Krishna C. Penumatsa, Stephen A. Wring. Serotonin and Pulmonary Hypertension; Sex and Drugs and ROCK and Rho. Compr Physiol 2022, 12: 1-16. doi: 10.1002/cphy.c220004