Abstract 12873: Clonal Hematopoiesis With JAK2V617F Promotes Pulmonary Hypertension Through ALK1

Rationale: Pulmonary hypertension (PH) is associated with hematological disorders by unclear multifactorial mechanisms. JAK2 V617F is the most frequent driver mutation among the myeloproliferative neoplasms and is recently identified in clonal hematopoiesis. However, the impact of clonal hematopoiesis on PH remains unknown. Objectives: To elucidate the mechanistic relevance of hematopoietic JAK2V617F in the development of PH. Methods: We applied experimental mouse models, mimicking hematological clinical scenarios using Jak2 V617F-transgenic (JAK2 V617F ) mice and recipient mice transplanted with JAK2 V617F bone marrow cells (JAK2 V617F recipients), exposed to chronic hypoxia to induce PH. The presence of JAK2 V617F was also examined prospectively in PH patients. Measurements and Main Results: Increases in right ventricular systolic pressure and right ventricular hypertrophy accompanied by pulmonary arterial structural remodeling after exposure to chronic hypoxia were significantly exacerbated in both JAK2 V617F mice which showed a myeloproliferative neoplasm-phenotype and JAK2 V617F recipients which modeled clonal hematopoiesis compared to corresponding controls. JAK2V617F-expressing neutrophils were specifically accumulated in pulmonary arterial regions, accompanied by increases in neutrophil-derived elastase activity and chemokines. RNA sequencing identified progressive upregulation of Acvrl1 (encoding ALK1) during the differentiation from bone marrow stem/progenitor cells peripherally into mature neutrophils of pulmonary arterial regions in the enrichment of JAK-STAT-related molecules by JAK2V617F. JAK2V617F-mediated STAT3 phosphorylation upregulated ALK1-Smad1/5/8 signaling. Strikingly, ALK1 inhibition completely rescued the development of PH in JAK2 V617F mice. Furthermore, clonal hematopoiesis with JAK2 V617F was significantly more common in PH patients than in healthy subjects. Conclusions: Our study reveals clonal hematopoiesis with JAK2V617F as a crucial factor that causally leads to PH through ALK1.

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Exogenous Ghrelin Attenuates the Progression of Chronic Hypoxia-Induced Pulmonary Hypertension in Conscious Rats

Endocrinology ◽

10.1210/en.2007-0833 ◽

2007 ◽

Vol 149 (1) ◽

pp. 237-244 ◽

Cited By ~ 34

Author(s):

Daryl O. Schwenke ◽

Takeshi Tokudome ◽

Mikiyasu Shirai ◽

Hiroshi Hosoda ◽

Takeshi Horio ◽

...

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Right Ventricular ◽

Endothelial Nitric Oxide Synthase ◽

Ventricular Hypertrophy ◽

Chronic Hypoxia ◽

Right Ventricular Hypertrophy ◽

Pulmonary Arterial ◽

Oxide Synthase ◽

Endothelial Nitric Oxide

Chronic exposure to hypoxia, a common adverse consequence of most pulmonary disorders, can lead to a sustained increase in pulmonary arterial pressure (PAP), right ventricular hypertrophy, and is, therefore, closely associated with heart failure and increased mortality. Ghrelin, originally identified as an endogenous GH secretagogue, has recently been shown to possess potent vasodilator properties, likely involving modulation of the vascular endothelium and its associated vasoactive peptides. In this study we hypothesized that ghrelin would impede the pathogenesis of pulmonary arterial hypertension during chronic hypoxia (CH). PAP was continuously measured using radiotelemetry, in conscious male Sprague Dawley rats, in normoxia and during 2-wk CH (10% O2). During this hypoxic period, rats received a daily sc injection of either saline or ghrelin (150 μg/kg). Subsequently, heart and lung samples were collected for morphological, histological, and molecular analyses. CH significantly elevated PAP in saline-treated rats, increased wall thickness of peripheral pulmonary arteries, and, consequently, induced right ventricular hypertrophy. In these rats, CH also led to the overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA within the lung. Exogenous ghrelin administration attenuated the CH-induced overexpression of endothelial nitric oxide synthase mRNA and protein, as well as endothelin-1 mRNA. Consequently, ghrelin significantly attenuated the development of pulmonary arterial hypertension, pulmonary vascular remodeling, and right ventricular hypertrophy. These results demonstrate the therapeutic benefits of ghrelin for impeding the pathogenesis of pulmonary hypertension and right ventricular hypertrophy, particularly in subjects prone to CH (e.g. pulmonary disorders).

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p53 Gene deficiency promotes hypoxia-induced pulmonary hypertension and vascular remodeling in mice

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00286.2010 ◽

2011 ◽

Vol 300 (5) ◽

pp. L753-L761 ◽

Cited By ~ 81

Author(s):

Shiro Mizuno ◽

Herman J. Bogaard ◽

Donatas Kraskauskas ◽

Aysar Alhussaini ◽

Jose Gomez-Arroyo ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Left Ventricle ◽

Right Ventricular ◽

Vascular Remodeling ◽

Ventricular Hypertrophy ◽

Chronic Hypoxia ◽

Hypoxic Exposure ◽

Arterial Remodeling ◽

Pulmonary Arterial ◽

The Right

Chronic hypoxia induces pulmonary arterial remodeling, resulting in pulmonary hypertension and right ventricular hypertrophy. Hypoxia has been implicated as a physiological stimulus for p53 induction and hypoxia-inducible factor-1α (HIF-1α). However, the subcellular interactions between hypoxic exposure and expression of p53 and HIF-1α remain unclear. To examine the role of p53 and HIF-1α expression on hypoxia-induced pulmonary arterial remodeling, wild-type (WT) and p53 knockout (p53KO) mice were exposed to either normoxia or hypoxia for 8 wk. Following chronic hypoxia, both genotypes demonstrated elevated right ventricular pressures, right ventricular hypertrophy as measured by the ratio of the right ventricle to the left ventricle plus septum weights, and vascular remodeling. However, the right ventricular systolic pressures, the ratio of the right ventricle to the left ventricle plus septum weights, and the medial wall thickness of small vessels were significantly greater in the p53KO mice than in the WT mice. The p53KO mice had lower levels of p21 and miR34a expression, and higher levels of HIF-1α, VEGF, and PDGF expression than WT mice following chronic hypoxic exposure. This was associated with a higher proliferating cell nuclear antigen expression of pulmonary artery in p53KO mice. We conclude that p53 plays a critical role in the mitigation of hypoxia-induced small pulmonary arterial remodeling. By interacting with p21 and HIF-1α, p53 may suppress hypoxic pulmonary arterial remodeling and pulmonary arterial smooth muscle cell proliferation under hypoxia.

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E-4010, a selective phosphodiesterase 5 inhibitor, attenuates hypoxic pulmonary hypertension in rats

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1999.277.2.l225 ◽

1999 ◽

Vol 277 (2) ◽

pp. L225-L232 ◽

Cited By ~ 6

Author(s):

Norihisa Hanasato ◽

Masahiko Oka ◽

Masashi Muramatsu ◽

Mayu Nishino ◽

Hideyuki Adachi ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Cardiac Output ◽

Arterial Pressure ◽

Right Ventricular ◽

Ventricular Hypertrophy ◽

Chronic Hypoxia ◽

Systemic Arterial Pressure ◽

Right Ventricular Hypertrophy ◽

Pulmonary Arterial

The purpose of this study was to determine whether E-4010, a newly synthesized potent and selective orally active phosphodiesterase (PDE) 5 inhibitor, would prevent the development of chronic hypoxia-induced pulmonary hypertension in rats. In conscious, pulmonary hypertensive rats, a single oral administration of E-4010 (1.0 mg/kg) caused an acute, long-lasting reduction in mean pulmonary arterial pressure (PAP), with no significant effects on systemic arterial pressure, cardiac output, and heart rate. In rats that received food containing 0.01 or 0.1% E-4010 during the 3-wk exposure to hypoxia, mean PAP was significantly decreased (mean PAP 24.0 ± 0.9, 16.2 ± 0.8, and 12.8 ± 0.5 mmHg in rats treated with 0, 0.01, and 0.1% E-4010-containing food, respectively), whereas mean systemic arterial pressure was unchanged and cardiac output was slightly increased compared with chronically hypoxic control rats. Right ventricular hypertrophy, medial wall thickness in pulmonary arteries corresponding to the respiratory and terminal bronchioles, and the degree of muscularization of more distal arteries were less severe in E-4010-treated rats. Long-term treatment with E-4010 caused an increase in cGMP levels in lung tissue and plasma but not in aortic tissue and no significant change in cAMP levels in either lung, aorta, or plasma. These results suggest that long-term oral treatment with E-4010 reduced the increase in PAP, right ventricular hypertrophy, and pulmonary arterial remodeling induced by exposure to chronic hypoxia, probably through increasing cGMP levels in the pulmonary vascular smooth muscle.

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Therapeutic hypercapnia prevents chronic hypoxia-induced pulmonary hypertension in the newborn rat

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00480.2005 ◽

2006 ◽

Vol 291 (5) ◽

pp. L912-L922 ◽

Cited By ~ 65

Author(s):

Crystal Kantores ◽

Patrick J. McNamara ◽

Lilian Teixeira ◽

Doreen Engelberts ◽

Prashanth Murthy ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Vascular Remodeling ◽

Chronic Hypoxia ◽

Antioxidant Properties ◽

Ventricular Performance ◽

Pulmonary Vascular Remodeling ◽

Beneficial Effects ◽

Arterial Resistance ◽

Pulmonary Arterial

Induction of hypercapnia by breathing high concentrations of carbon dioxide (CO2) may have beneficial effects on the pulmonary circulation. We tested the hypothesis that exposure to CO2 would protect against chronic pulmonary hypertension in newborn rats. Atmospheric CO2 was maintained at <0.5% (normocapnia), 5.5%, or 10% during exposure from birth for 14 days to normoxia (21% O2) or moderate hypoxia (13% O2). Pulmonary vascular and hemodynamic abnormalities in animals exposed to chronic hypoxia included increased pulmonary arterial resistance, right ventricular hypertrophy and dysfunction, medial thickening of pulmonary resistance arteries, and distal arterial muscularization. Exposure to 10% CO2 (but not to 5.5% CO2) significantly attenuated pulmonary vascular remodeling and increased pulmonary arterial resistance in hypoxia-exposed animals ( P < 0.05), whereas both concentrations of CO2 normalized right ventricular performance. Exposure to 10% CO2 attenuated increased oxidant stress induced by hypoxia, as quantified by 8-isoprostane content in the lung, and prevented upregulation of endothelin-1, a critical mediator of pulmonary vascular remodeling. We conclude that hypercapnic acidosis has beneficial effects on pulmonary hypertension and vascular remodeling induced by chronic hypoxia, which we speculate derives from antioxidant properties of CO2 on the lung and consequent modulating effects on the endothelin pathway.

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Heme biosynthesis modulation via δ-aminolevulinic acid administration attenuates chronic hypoxia-induced pulmonary hypertension

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00155.2014 ◽

2015 ◽

Vol 308 (7) ◽

pp. L719-L728 ◽

Cited By ~ 16

Author(s):

Raed Alhawaj ◽

Dhara Patel ◽

Melissa R. Kelly ◽

Dong Sun ◽

Michael S. Wolin

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Chronic Hypoxia ◽

Aminolevulinic Acid ◽

Pulmonary Arteries ◽

Protoporphyrin Ix ◽

Heme Biosynthesis ◽

Mitochondrial Superoxide ◽

Stat3 Phosphorylation ◽

Biosynthesis Modulation

This study examines how heme biosynthesis modulation with δ-aminolevulinic acid (ALA) potentially functions to prevent 21-day hypoxia (10% oxygen)-induced pulmonary hypertension in mice and the effects of 24-h organoid culture with bovine pulmonary arteries (BPA) with the hypoxia and pulmonary hypertension mediator endothelin-1 (ET-1), with a focus on changes in superoxide and regulation of micro-RNA 204 (miR204) expression by src kinase phosphorylation of signal transducer and activator of transcription-3 (STAT3). The treatment of mice with ALA attenuated pulmonary hypertension (assessed through echo Doppler flow of the pulmonary valve, and direct measurements of right ventricular systolic pressure and right ventricular hypertrophy), increases in pulmonary arterial superoxide (detected by lucigenin), and decreases in lung miR204 and mitochondrial superoxide dismutase (SOD2) expression. ALA treatment of BPA attenuated ET-1-induced increases in mitochondrial superoxide (detected by MitoSox), STAT3 phosphorylation, and decreases in miR204 and SOD2 expression. Because ALA increases BPA protoporphyrin IX (a stimulator of guanylate cyclase) and cGMP-mediated protein kinase G (PKG) activity, the effects of the PKG activator 8-bromo-cGMP were examined and found to also attenuate the ET-1-induced increase in superoxide. ET-1 increased superoxide production and the detection of protoporphyrin IX fluorescence, suggesting oxidant conditions might impair heme biosynthesis by ferrochelatase. However, chronic hypoxia actually increased ferrochelatase activity in mouse pulmonary arteries. Thus, a reversal of factors increasing mitochondrial superoxide and oxidant effects that potentially influence remodeling signaling related to miR204 expression and perhaps iron availability needed for the biosynthesis of heme by the ferrochelatase reaction could be factors in the beneficial actions of ALA in pulmonary hypertension.

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The Role of Collagen Synthesis in Ventricular and Vascular Adaptation to Hypoxic Pulmonary Hypertension

Journal of Biomechanical Engineering ◽

10.1115/1.4023480 ◽

2013 ◽

Vol 135 (2) ◽

Cited By ~ 28

Author(s):

David Schreier ◽

Timothy Hacker ◽

Gouqing Song ◽

Naomi Chesler

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Artery ◽

Right Ventricular ◽

Collagen Synthesis ◽

Chronic Hypoxia ◽

Coupling Efficiency ◽

Pulmonary Arteries ◽

Collagen Accumulation ◽

The Impact ◽

Rv Function

Pulmonary arterial hypertension (PAH) is a rapidly fatal disease in which mortality is typically due to right ventricular (RV) failure. An excellent predictor of mortality in PAH is proximal pulmonary artery stiffening, which is mediated by collagen accumulation in hypoxia-induced pulmonary hypertension (HPH) in mice. We sought to investigate the impact of limiting vascular and ventricular collagen accumulation on RV function and the hemodynamic coupling efficiency between the RV and pulmonary vasculature. Inbred mice were exposed to chronic hypoxia for 10 days with either no treatment (HPH) or with treatment with a proline analog that impairs collagen synthesis (CHOP-PEG; HPH + CP). Both groups were compared to control mice (CTL) exposed only to normoxia (no treatment). An admittance catheter was used to measure pressure-volume loops at baseline and during vena cava occlusion, with mice ventilated with either room air or 8% oxygen, from which pulmonary hemodynamics, RV function, and ventricular-vascular coupling efficiency (ηvvc) were calculated. Proline analog treatment limited increases in RV afterload (neither effective arterial elastance Ea nor total pulmonary vascular resistance significantly increased compared to CTL with CHOP-PEG), limited the development of pulmonary hypertension (CHOP-PEG reduced right ventricular systolic pressure by 10% compared to HPH, p < 0.05), and limited RV hypertrophy (CHOP-PEG reduced RV mass by 18% compared to HPH, p < 0.005). In an acutely hypoxic state, treatment improved RV function (CHOP-PEG increased end-systolic elastance Ees by 43%, p < 0.05) and maintained ηvvc at control, room air levels. CHOP-PEG also decreased lung collagen content by 12% measured biochemically compared to HPH (p < 0.01), with differences evident in large and small pulmonary arteries by histology. Our results demonstrate that preventing new collagen synthesis limits pulmonary hypertension development by reducing collagen accumulation in the pulmonary arteries that affect RV afterload. In particular, the proline analog limited structural and functional changes in distal pulmonary arteries in this model of early and somewhat mild pulmonary hypertension. We conclude that collagen plays an important role in small pulmonary artery remodeling and, thereby, affects RV structure and function changes induced by chronic hypoxia.

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The unexpected role of PI3-kinase gamma in pulmonary hypertension

European Heart Journal ◽

10.1093/ehjci/ehaa946.3811 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

L Feik ◽

E Berghausen ◽

M Zierden ◽

E Hirsch ◽

S Baldus ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Specific Inhibitor ◽

Left Ventricular ◽

Brdu Incorporation ◽

Pulmonary Vascular Disease ◽

High Morbidity ◽

Pulmonary Arterial ◽

The Impact

Abstract Introduction Pulmonary hypertension (PH) is a pulmonary vascular disease that is associated with unacceptably high morbidity and mortality. PH is characterized by chronically increased pulmonary arterial pressure, increased pulmonary vascular resistance and right ventricular (RV) dysfunction and hypertrophy. Underlying mechanisms include increased proliferation and reduced apoptosis of both vascular smooth muscle cells (SMC) and endothelial cells (EC), as well as dysregulated immune responses. We have previously shown that class IA phosphatidylinositol-3-kinase (PI3K) isoforms, activated via receptor tyrosine kinases, are critically involved in the pathogenesis of PH. However, recent findings suggest that the class IB isoform PI3Kγ, which is activated downstream of G protein coupled receptors, is also important. It has been shown that PI3Kγ is involved in numerous processes that promote both vascular remodelling and maladaptive cardiac hypertrophy, including leukocyte recruitment, expression of proinflammatory chemokines and cytokines, as well as SMC and EC proliferation and survival. Therefore, the aim of our study was to investigate the role of PI3Kγ in the pathogenesis of PH. Methods The impact of PI3Kγ on the pathogenesis of PH was analysed in vivo using mice expressing a catalytically inactive form of PI3Kγ (PI3KγKD/KD) in the hypoxia-induced mouse model of PH. Mice were kept at 10%O2 (HOX) for 21 days or left under normoxic conditions (NOX). Subsequently, systolic right ventricular pressure (RVSP) was measured with a pressure catheter. RV hypertrophy was expressed as the ratio of RV weight to left ventricular + septum weight. Migration and proliferation of human pulmonary arterial SMC (hPASMC) as well as EC (hMVEC) were analysed using a PI3Kγ isoform-specific inhibitor (AS605240 [0.1; 0.3; 1μM]). Chemotaxis was determined by means of a modified Boyden chamber, and proliferation was quantified by a Bromodeoxyuridine (BrdU) incorporation assay. Results Whereas PI3Kγ inactivation had no effect on NOX animals, hypoxia led to increased RVSP and RV hypertrophy in WT animals (34.67±2.02 mmHg; 0.38±0.087) which were unexpectedly further increased in PI3KγKD/KD mice (37.67±1.3 mmHg, p=0.0104 vs. HOX WT; 0.47±0.06, p=0.0155 vs. HOX WT). Heart rate and systemic blood pressure remained unchanged. Inhibition of PI3Kγ by means of AS605240 did not affect proliferation of hPASMC and hMVEC, induced by multiple stimuli (FCS [10%], PDGF-BB [30ng/ml], or CXCL12 [100ng/ml], VEGF [50ng/ml]), respectively. However, FCS-induced migration of these cells was significantly reduced by AS605240 [0.3μM] (p<0.05). Conclusion Contrary to our expectations, the results show that kinase inactivation of PI3Kγ was not able to attenuate the pathogenesis of PH, but surprisingly led to a significant increase without critically changing cellular responses of SMC and EC. Therefore, our results indicate an unexpected protective effect of PI3Kγ on PH. Funding Acknowledgement Type of funding source: None

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Interleukin-6 trans-signaling contributes to chronic hypoxia-induced pulmonary hypertension

Pulmonary Circulation ◽

10.1177/2045894018780734 ◽

2018 ◽

Vol 8 (3) ◽

pp. 204589401878073 ◽

Cited By ~ 8

Author(s):

Levi D. Maston ◽

David T. Jones ◽

Wieslawa Giermakowska ◽

Thomas C. Resta ◽

Juan Ramiro-Diaz ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Right Ventricular ◽

Interleukin 6 ◽

Chronic Hypoxia ◽

Systolic Pressure ◽

Specific Inhibitor ◽

Arterial Remodeling ◽

Cell Growth And Migration ◽

Pulmonary Arterial ◽

And Migration

Interleukin-6 (IL-6) is a pleotropic cytokine that signals through the membrane-bound IL-6 receptor (mIL-6R) to induce anti-inflammatory (“classic-signaling”) responses. This cytokine also binds to the soluble IL-6R (sIL-6R) to promote inflammation (“trans-signaling”). mIL-6R expression is restricted to hepatocytes and immune cells. Activated T cells release sIL-6R into adjacent tissues to induce trans-signaling. These cellular actions require the ubiquitously expressed membrane receptor gp130. Reports show that IL-6 is produced by pulmonary arterial smooth muscle cells (PASMCs) exposed to hypoxia in culture as well as the medial layer of the pulmonary arteries in mice exposed to chronic hypoxia (CH), and IL-6 knockout mice are protected from CH-induced pulmonary hypertension (PH). IL-6 has the potential to contribute to a broad array of downstream effects, such as cell growth and migration. CH-induced PH is associated with increased proliferation and migration of PASMCs to previously non-muscularized vessels of the lung. We tested the hypothesis that IL-6 trans-signaling contributes to CH-induced PH and arterial remodeling. Plasma levels of sgp130 were significantly decreased in mice exposed to CH (380 mmHg) for five days compared to normoxic control mice (630 mmHg), while sIL-6R levels were unchanged. Consistent with our hypothesis, mice that received the IL-6 trans-signaling-specific inhibitor sgp130Fc, a fusion protein of the soluble extracellular portion of gp130 with the constant portion of the mouse IgG1 antibody, showed attenuation of CH-induced increases in right ventricular systolic pressure, right ventricular and pulmonary arterial remodeling as compared to vehicle (saline)-treated control mice. In addition, PASMCs cultured in the presence of IL-6 and sIL-6R showed enhanced migration but not proliferation compared to those treated with IL-6 or sIL-6R alone or in the presence of sgp130Fc. These results indicate that IL-6 trans-signaling contributes to pulmonary arterial cell migration and CH-induced PH.

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Sex Dimorphism in Pulmonary Hypertension: The Role of the Sex Chromosomes

Antioxidants ◽

10.3390/antiox10050779 ◽

2021 ◽

Vol 10 (5) ◽

pp. 779

Author(s):

Daria S. Kostyunina ◽

Paul McLoughlin

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Pulmonary Vascular Resistance ◽

Vascular Resistance ◽

Sex Chromosomes ◽

Bone Morphogenetic Protein 2 ◽

Sex Dimorphism ◽

Pulmonary Arterial ◽

The Impact

Pulmonary hypertension (PH) is a condition characterised by an abnormal elevation of pulmonary artery pressure caused by an increased pulmonary vascular resistance, frequently leading to right ventricular failure and reduced survival. Marked sexual dimorphism is observed in patients with pulmonary arterial hypertension, a form of pulmonary hypertension with a particularly severe clinical course. The incidence in females is 2–4 times greater than in males, although the disease is less severe in females. We review the contribution of the sex chromosomes to this sex dimorphism highlighting the impact of proteins, microRNAs and long non-coding RNAs encoded on the X and Y chromosomes. These genes are centrally involved in the cellular pathways that cause increased pulmonary vascular resistance including the production of reactive oxygen species, altered metabolism, apoptosis, inflammation, vasoconstriction and vascular remodelling. The interaction with genetic mutations on autosomal genes that cause heritable pulmonary arterial hypertension such as bone morphogenetic protein 2 (BMPR2) are examined. The mechanisms that can lead to differences in the expression of genes located on the X chromosomes between females and males are also reviewed. A better understanding of the mechanisms of sex dimorphism in this disease will contribute to the development of more effective therapies for both women and men.

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