ArticlePulmonary circulation2016
The serotonin transporter promotes a pathological estrogen metabolic pathway in pulmonary hypertension via cytochrome P450 1B1.
Article in Pulmonary circulation, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 38 citations in OpenAlex.
- CYP1B1 Mediates Cigarette Smoke-Induced Lipid Accumulation in Alveolar Type 2 Cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Estrogen and Cyp1b1 Regulate Pparγ in Pulmonary Hypertension Through a Ubiquitin-Dependent Mechanism.Pulmonary circulation · 2025Article
- A pilot study to examine association of BMI with functional class and 6 min walk distance in idiopathic and heritable PAH: Possible association with estrogen metabolism.Pulmonary circulation · 2022Article
- Bioactivities and mechanisms of natural medicines in the management of pulmonary arterial hypertension.Chinese medicine · 2022Review
- Pulmonary Arterial Hypertension: Emerging Principles of Precision Medicine across Basic Science to Clinical Practice.Reviews in cardiovascular medicine · 2022Article
- Sex and gender in pulmonary arterial hypertension.European respiratory review : an official journal of the European Respiratory Society · 2021Review
- Sex-dependent right ventricular hypertrophic gene changes after methamphetamine treatment in mice.European journal of pharmacology · 2021Article
- Sex Differences in Pulmonary Hypertension.Frontiers in aging · 2021Review
- Roles of Genetic Predisposition in the Sex Bias of Pulmonary Pathophysiology, as a Function of Estrogens : Sex Matters in the Prevalence of Lung Diseases.Advances in experimental medicine and biology · 2021Article
- Cytochrome P4501B1 in bone marrow is co-expressed with key markers of mesenchymal stem cells. BMS2 cell line models PAH disruption of bone marrow niche development functions.Toxicology and applied pharmacology · 2020Article
- Estrogen administration reduces the risk of pulmonary arterial hypertension by modulating the miR-133a signaling pathways in rats.Gene therapy · 2020Article
- Cytochrome P450 Epoxygenase-Dependent Activation of TRPV4 Channel Participates in Enhanced Serotonin-Induced Pulmonary Vasoconstriction in Chronic Hypoxic Pulmonary Hypertension.Analytical cellular pathology (Amsterdam) · 2020Article
- Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension.International journal of molecular sciences · 2019Review
- Sex, Gender, and Sex Hormones in Pulmonary Hypertension and Right Ventricular Failure.Comprehensive Physiology · 2019Review
- Obesity alters oestrogen metabolism and contributes to pulmonary arterial hypertension.The European respiratory journal · 2019Article
- Analysis of Angiotensin Converting Enzyme, Endothelial Nitric Oxide Synthase & Serotonin Gene Polymorphisms among Atrial Septal Defect Subjects with and without Pulmonary Arterial Hypertension.Journal of cardiovascular development and disease · 2018Article
- Role of the Aryl Hydrocarbon Receptor in Sugen 5416-induced Experimental Pulmonary Hypertension.American journal of respiratory cell and molecular biology · 2018Article
- Sexually Dimorphic Regulation of EET Synthesis and Metabolism: Roles of Estrogen.Frontiers in pharmacology · 2018Article
- Serotonin Signaling Through the 5-HTArteriosclerosis, thrombosis, and vascular biology · 2017Article
- High-throughput analysis reveals novel maternal germline RNAs crucial for primordial germ cell preservation and proper migration.Development (Cambridge, England) · 2017Article
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Pulmonary arterial hypertension (PAH) is a devastating vasculopathy that predominates in women and has been associated with dysregulated estrogen and serotonin signaling. Overexpression of the serotonin transporter (SERT(+)) in mice results in an estrogen-dependent development of pulmonary hypertension (PH). Estrogen metabolism by cytochrome P450 1B1 (CYP1B1) contributes to the pathogenesis of PAH, and serotonin can increase CYP1B1 expression in human pulmonary arterial smooth muscle cells (hPASMCs). We hypothesized that an increase in intracellular serotonin via increased SERT expression may dysregulate estrogen metabolism via CYP1B1 to facilitate PAH. Consistent with this hypothesis, we found elevated lung CYP1B1 protein expression in female SERT(+) mice accompanied by PH, which was attenuated by the CYP1B1 inhibitor 2,3',4,5'-tetramethoxystilbene (TMS). Lungs from female SERT(+) mice demonstrated an increase in oxidative stress that was marked by the expression of 8-hydroxyguanosine; however, this was unaffected by CYP1B1 inhibition. SERT expression was increased in monocrotaline-induced PH in female rats; however, TMS did not reverse PH in monocrotaline-treated rats but prolonged survival. Stimulation of hPASMCs with the CYP1B1 metabolite 16α-hydroxyestrone increased cellular proliferation, which was attenuated by an inhibitor (MPP) of estrogen receptor alpha (ERα) and a specific ERα antibody. Thus, increased intracellular serotonin caused by increased SERT expression may contribute to PAH pathobiology by dysregulation of estrogen metabolic pathways via increased CYP1B1 activity. This promotes PASMC proliferation by the formation of pathogenic metabolites of estrogen that mediate their effects via ERα. Our studies indicate that targeting this pathway in PAH may provide a promising antiproliferative therapeutic strategy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.