Characterization of the vasodilatory action of testosterone in the human pulmonary circulation

Smith, A.; Bennett, Robert T.; Jones, T Hugh; Cowen, Mike; Channer, Kevin S.; Jones, Richard D.

doi:10.2147/vhrm.s3995

Cited by 33 publications

(19 citation statements)

References 26 publications

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“…The co‐IP study confirmed the existence of a multiprotein complex formed by an interaction between hsp90, CSE and NR3C4. Furthermore, in line with the current literature, T decreased hsp90/NR3C4 binding (Falkenstein et al ., ; Smith et al ., ). These results provide novel information about the intracellular localization of CSE and its interaction with hsp90 and NR3C4, which is an essential requirement for testosterone‐induced increase in H 2 S production.…”

Section: Discussionmentioning

confidence: 98%

Crucial role of androgen receptor in vascular H₂S biosynthesis induced by testosterone

Brancaleone

Vellecco

Matassa

et al. 2014

British J Pharmacology

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Background and Purpose Hydrogen sulphide (H2S) is a gaseous mediator strongly involved in cardiovascular homeostasis, where it provokes vasodilatation. Having previously shown that H2S contributes to testosterone‐induced vasorelaxation, here we aim to uncover the mechanisms underlying this effect. Experimental Approach H2S biosynthesis was evaluated in rat isolated aortic rings following androgen receptor (NR3C4) stimulation. Co‐immunoprecipitation and surface plasmon resonance analysis were performed to investigate mechanisms involved in NR3C4 activation. Key Results Pretreatment with NR3C4 antagonist nilutamide prevented testosterone‐induced increase in H2S and reduced its vasodilator effect. Androgen agonist mesterolone also increased H2S and induced vasodilatation; effects attenuated by the selective cystathionine‐γ lyase (CSE) inhibitor propargylglycine. The NR3C4‐multicomplex‐derived heat shock protein 90 (hsp90) was also involved in this effect; its specific inhibitor geldanamycin strongly reduced testosterone‐induced H2S production. Neither progesterone nor 17‐β‐oestradiol induced H2S release. Furthermore, we demonstrated that CSE, the main vascular H2S‐synthesizing enzyme, is physically associated with the NR3C4/hsp90 complex and the generation of such a ternary system represents a key event leading to CSE activation. Finally, H2S levels in human blood collected from male healthy volunteers were higher than those in female samples. Conclusions and Implications We demonstrated that selective activation of the NR3C4 is essential for H2S biosynthesis within vascular tissue, and this event is based on the formation of a ternary complex between cystathionine‐γ lyase, NR3C4and hsp90. This novel molecular mechanism operating in the vasculature, corroborated by higher H2S levels in males, suggests that the L‐cysteine/CSE/H2S pathway may be preferentially activated in males leading to gender‐specific H2S biosynthesis. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6

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Section: Discussionmentioning

confidence: 98%

Crucial role of androgen receptor in vascular H₂S biosynthesis induced by testosterone

Brancaleone

Vellecco

Matassa

et al. 2014

British J Pharmacology

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“…Testosterone induces vasodilation in the isolated rat pulmonary vasculature most likely via calcium antagonistic effects (131), and it has been confirmed that in isolated human pulmonary arteries, these vasodilatory effects are independent of gender (132). In rodents, testosterone is an even more potent pulmonary vasodilator than estradiol (133).…”

Section: The Effects Of Progestins and Androgens In Experimental Pahmentioning

confidence: 93%

Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Tofovic

2010

Journal of Cardiovascular Pharmacology

102

113

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Severe pulmonary arterial hypertension (PAH) is characterized by clustered proliferation of endothelial cells in the lumina of small size pulmonary arteries resulting in concentric obliteration of the lumina and formation of complex vascular structures known as plexiform lesions. This debilitating disease occurs more frequently in women, yet both animal studies in classical models of PAH and limited clinical data suggest protective effects of estrogens: the estrogen paradox in pulmonary hypertension. Little is known about the role of estrogens in PAH, but one line of evidence strongly suggests that the vascular protective effects of 17β-estradiol (estradiol; E2) are mediated largely by its downstream metabolites. Estradiol is metabolized to 2-hydroxyestradiol (2HE) by CYP1A1/CYP1B1, and 2HE is converted to 2-methoxyestradiol (2ME) by catechol-Omethyl transferase. 2ME is extensively metabolized to 2-methoxyestrone, a metabolite that lacks biologic activity but which may be converted back to 2ME. 2ME has no estrogenic activity and its effects are mediated by estrogen receptors-independent mechanism(s). Notably, in systemic and pulmonary vascular endothelial cells, smooth muscle cells, and fibroblasts 2ME exerts stronger anti-mitotic effects than E2 itself. E2 and 2ME, despite having similar effects on other cardiovascular cells, have opposing effects on endothelial cells; that is, in endothelial cells, E2 is pro-mitogenic, pro-angiogenic and anti-apoptotic, whereas 2ME is antimitogenic, anti-angiogenic and pro-apoptotic. This may have significant ramifications in severe PAH that involves uncontrolled proliferation of monoclonal, apoptosis resistant endothelial cells. Based on its cellular effects, 2ME should be expected to attenuate the progression of disease and provide protection in severe PAH. In contrast, E2, due to its mitogenic, angiogenic, and anti-apoptotic effects (otherwise desirable in normal, quiescent endothelial cells), may even adversely affect endothelial remodeling in PAH and this may be even more significant if the E2's effects on injured endothelium are not opposed by 2ME (e.g., in the event of reduced E2 conversion to 2ME due to hypoxia, inflammation, drugs, environmental factors, or genetic polymorphism of metabolizing enzymes). This review focuses on the effects of estrogens and their metabolites on pulmonary vascular pathobiology and the development of experimental PAH, and offers potential explanation for the estrogen paradox in PAH. Furthermore, we propose that unbalanced estradiol metabolism may lead to the development of PAH. Recent animal data and studies in patients with PAH support this concept.Corresponding Author: Stevan P. Tofovic M.D., Ph.D. FAHA FASN Division of Pulmonary, Allergy and Critical Care Medicine and Vascular Medicine Institute, Department of Medicine University of Pittsburgh School of Medicine Bridge side 542 100 Technology Drive, Pittsburgh, PA 15219 FAX +412-624-5070 Phone +412-648-3363 tofovic@dom.pitt.edu. This is a PDF file of an unedited manuscript that ...

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“…Testosterone is also a potent vasodilator in isolated human pulmonary vasculature, an effect that is independent of gender (Smith et al ., ; Rowell et al ., ). It is in fact a more potent vasodilator than oestrogen in this vascular bed (English et al ., ).…”

Section: Androgens and Pahmentioning

confidence: 98%

Pulmonary arterial hypertension: basis of sex differences in incidence and treatment response

Mair

Johansen

Wright

et al. 2014

British J Pharmacology

101

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Pulmonary arterial hypertension (PAH) is a complex disease characterized by elevated pulmonary arterial pressure, pulmonary vascular remodelling and occlusive pulmonary vascular lesions, leading to right heart failure. Evidence from recent epidemiological studies suggests the influence of gender on the development of PAH with an approximate female to male ratio of 4:1, depending on the underlying disease pathology. Overall, the therapeutic strategy for PAH remains suboptimal with poor survival rates observed in both genders. Endogenous sex hormones, in particular 17β oestradiol and its metabolites, have been implicated in the development of the disease; however, the influence of sex hormones on the underlying pathobiology remains controversial. Further understanding of the influence of sex hormones on the normal and diseased pulmonary circulation will be critical to our understanding the pathology of PAH and future therapeutic strategies. In this review, we will discuss the influence of sex hormones on the development of PAH and address recent controversies. LINKED ARTICLESThis article is part of a themed section on Biological Sex and Cardiovascular Pharmacology. To view the other articles in this section visit http://dx.doi.org/10. 1111/bph.2014.171.issue-3 Abbreviations AR, androgen receptor; BMPR2, bone morphogenetic protein receptor 2; CYP19A1, aromatase; CYP1B1, cytochrome P450 1B1; DHEA, dehydroepiandosterone; DHT, dihydrotestosterone; ER, oestrogen receptor; ERα, oestrogen receptor alpha; ERβ, oestrogen receptor beta; ET-1, endothelin-1; GPER, G protein-coupled oestrogen receptor; PAH, pulmonary arterial hypertension; PASMC, pulmonary artery smooth muscle cell; SERT, serotonin transporter; Su-Hx, SUGEN hypoxic; Tph1, tryptophan hydroxylase 1 Pulmonary arterial hypertension (PAH) is a progressive disease leading to right heart failure. Recent epidemiological data reports an increased incidence of PAH among females compared to males. For example, in the UK/Ireland and the USA, the percentage of female patients is 70 and 80% respectively (Badesch et al., 2010;Ling et al., 2012). There is mounting evidence to suggest that oestrogen and its metabolites may influence the pathogenesis of PAH. Here, we will examine the pathology, current therapies and the basis for gender differences in PAH, considering evidence gathered from both patient data and animal studies. Pulmonary arterial hypertensionPAH is defined by vascular remodelling and complex vascular lesion formation arising from the accelerated proliferation of pulmonary endothelial, smooth muscle and fibroblast cells (Rabinovitch, 2008). Clinically, the disease is defined as a mean pulmonary artery pressure of >25 mmHg at rest or >30 mmHg during exercise. Symptoms are often non-specific, including fatigue, exertional dyspnoea, oedema and syncope and as a result diagnosis is frequently delayed until the disease is well established.The main genetic defect associated with PAH is a mutation in the gene encoding bone morphogenetic protein receptor 2 (BMPR2). Ge...

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Characterization of the vasodilatory action of testosterone in the human pulmonary circulation

Cited by 33 publications

References 26 publications

Crucial role of androgen receptor in vascular H₂S biosynthesis induced by testosterone

Crucial role of androgen receptor in vascular H₂S biosynthesis induced by testosterone

Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Pulmonary arterial hypertension: basis of sex differences in incidence and treatment response

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Characterization of the vasodilatory action of testosterone in the human pulmonary circulation

Cited by 33 publications

References 26 publications

Crucial role of androgen receptor in vascular H2S biosynthesis induced by testosterone

Crucial role of androgen receptor in vascular H2S biosynthesis induced by testosterone

Estrogens and Development of Pulmonary Hypertension: Interaction of Estradiol Metabolism and Pulmonary Vascular Disease

Pulmonary arterial hypertension: basis of sex differences in incidence and treatment response

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Product

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Crucial role of androgen receptor in vascular H₂S biosynthesis induced by testosterone

Crucial role of androgen receptor in vascular H₂S biosynthesis induced by testosterone