Intrauterine Growth Restriction Programs Intergenerational Transmission of Pulmonary Arterial Hypertension and Endothelial Dysfunction via Sperm Epigenetic Modifications

Intrauterine life represents a window of phenotypic plasticity which carries consequences for later health in adulthood as well as health of subsequent generations. Intrauterine growth-restricted fetuses (intrauterine growth restriction [IUGR]) have a higher risk of pulmonary arterial hypertension in adulthood. Endothelial dysfunction, characterized by hyperproliferation, invasive migration, and disordered angiogenesis, is a hallmark of pulmonary arterial hypertension pathogenesis. Growing evidence suggests that intergenerational transmission of disease, including metabolic syndrome, can be induced by IUGR. Epigenetic modification of the paternal germline is implicated in this transmission. However, it is unclear whether offspring of individuals born with IUGR are also at risk of developing pulmonary arterial hypertension and endothelial dysfunction. Using a model of maternal caloric restriction to induce IUGR, we found that first and second generations of IUGR exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. Moreover, in 2 generations, PVECs-derived ET-1 (endothelin-1) was activated by IUGR and hypoxia, and its knockdown mitigated PVECs dysregulation. Most interestingly, within ET-1 first intron, reduced DNA methylation and enhanced tri-methylation of lysine 4 on histone H3 were observed in PVECs and sperm of first generation of IUGR, with DNA demethylation in PVECs of second generation of IUGR. These results suggest that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension–like pathophysiological features in adulthood.

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Aberrant Chloride Intracellular Channel 4 Expression Contributes to Endothelial Dysfunction in Pulmonary Arterial Hypertension

Circulation ◽

10.1161/circulationaha.113.006797 ◽

2014 ◽

Vol 129 (17) ◽

pp. 1770-1780 ◽

Cited By ~ 35

Author(s):

Beata Wojciak-Stothard ◽

Vahitha B. Abdul-Salam ◽

Ka Hou Lao ◽

Hilda Tsang ◽

David C. Irwin ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Endothelial Dysfunction ◽

Arterial Hypertension ◽

Pulmonary Arterial ◽

Intracellular Channel

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Peripheral Arterial Stiffness and Endothelial Dysfunction in Idiopathic and Scleroderma Associated Pulmonary Arterial Hypertension

The Journal of Rheumatology ◽

10.3899/jrheum.081088 ◽

2009 ◽

Vol 36 (5) ◽

pp. 970-975 ◽

Cited By ~ 44

Author(s):

NIR PELED ◽

DAVID SHITRIT ◽

BENJAMIN D. FOX ◽

DEKEL SHLOMI ◽

ANAT AMITAL ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Endothelial Dysfunction ◽

Arterial Stiffness ◽

Endothelial Function ◽

Arterial Hypertension ◽

Systolic Pressure ◽

Vascular Involvement ◽

Pulmonary Pressure ◽

Pulmonary Arterial ◽

Peripheral Arterial

Objective.Pulmonary endothelial dysfunction and increased reflection of pulmonary pressure waves have been reported in pulmonary arterial hypertension (PAH). However, the systemic vascular involvement is not fully understood. Our study focused on the systemic arterial stiffness and endothelial involvement in idiopathic and scleroderma associated PAH.Methods.Peripheral arterial stiffness and endothelial function were evaluated in 38 patients with idiopathic (n = 28) and scleroderma associated (n = 10) PAH, and 21 control subjects (13 healthy; 8 with scleroderma and normal pulmonary pressure). All participants underwent clinical and cardiopulmonary evaluation. Arterial stiffness was measured through the fingertip tonometry derived augmentation index (AI), which is the boost increase in the late systolic pressure wave after the initial systolic shoulder. Endothelial function was measured by forearm blood flow dilatation response to brachial artery occlusion by a noninvasive plethysmograph (EndoPAT 2000), which is associated with nitric oxide-dependent vasodilatation and yields a peripheral arterial tone (PAT) ratio.Results.Mean systolic pulmonary pressure was 70.5 ± 21.6 mm Hg (idiopathic-PAH) and 69.3 ± 20 mm Hg (scleroderma-PAH). AI was higher in scleroderma patients (10.5% ± 19.6% in healthy controls, 9.0% ± 21.5% in idiopathic-PAH, 20.1% ± 19.1% in scleroderma-PAH, and 24.4% ± 18.9% in scleroderma-controls; nonsignificant). PAT ratio was significantly lower (p < 0.05) than control values in idiopathic-PAH and scleroderma-PAH (PAT ratio: control 2.20 ± 0.25; idiopathic 1.84 ± 0.51; scleroderma 1.66 ± 0.66). AI was not correlated to endothelial dysfunction. There were no differences between the 2 PAH patient groups in age, body mass index, New York Heart Association classification, or 6-min walk test.Conclusion.Our study shows a trend towards increased arterial stiffness in scleroderma (nonsignificant), and also peripheral endothelial dysfunction in idiopathic-PAH and in scleroderma-PAH. These findings suggest involvement of different vessels in scleroderma-PAH compared to idiopathic-PAH.

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Peripheral endothelial dysfunction in patients with pulmonary arterial hypertension

Respiratory Medicine ◽

10.1016/j.rmed.2008.06.014 ◽

2008 ◽

Vol 102 (12) ◽

pp. 1791-1796 ◽

Cited By ~ 35

Author(s):

Nir Peled ◽

Daniele Bendayan ◽

David Shitrit ◽

Ben Fox ◽

Liora Yehoshua ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Endothelial Dysfunction ◽

Arterial Hypertension ◽

Pulmonary Arterial

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The FGL2 prothrombinase contributes to the pathological process of experimental pulmonary hypertension

Journal of Applied Physiology ◽

10.1152/japplphysiol.00396.2019 ◽

2019 ◽

Vol 127 (6) ◽

pp. 1677-1687

Author(s):

Cheng Fan ◽

Jue Wang ◽

Chaoqin Mao ◽

Wenzhu Li ◽

Kun Liu ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Pulmonary Arterial Hypertension ◽

Endothelial Dysfunction ◽

Arterial Hypertension ◽

Vascular Remodeling ◽

Thrombus Formation ◽

Idiopathic Pulmonary Arterial Hypertension ◽

Potential Therapeutic Target ◽

Pulmonary Arterial

In situ thrombus formation is one of the major pathological features of pulmonary hypertension (PH). The mechanism of in situ thrombosis has not been clearly identified. Fibrinogen-like protein 2 (FGL2) prothrombinase is an immune coagulant that can cleave prothrombin to thrombin, which then converts fibrinogen into fibrin. This mechanism triggers in situ thrombus formation directly, bypassing both the intrinsic and extrinsic coagulation pathways. FGL2 prothrombinase is mainly expressed in endothelial cells and mediates multiple pathological processes. This implies that it may also play a role in PH. In this study, we examined the expression of FGL2 in idiopathic pulmonary arterial hypertension (IPAH) patients, and in monocrotaline-induced rat and hypoxia-induced mouse PH models. Fgl2−/− mice were used to evaluate the development of PH and explore associated pathological changes. These included in situ thrombosis, vascular remodeling, and endothelial apoptosis. Following these analyses, we examined possible signaling pathways downstream of FGL2 in PH. We show FGL2 is upregulated in pulmonary vascular endothelium in human IPAH and in two animal PH models. Genetic knockout of Fgl2 limited the development of PH, indicated by decreased in situ thrombus formation, less vascular remodeling, and reduced endothelial dysfunction. In addition, loss of FGL2 downregulated PAR1 (proteinase-activated receptor 1) expression and decreased the overactivation and consumption of platelets in hypoxia-induced PH. These results indicate FGL2 participate in the development of PH and loss of FGL2 could attenuate PH by reducing in situ thrombosis and suppressing PAR1 signaling. Thus we provide evidence that suggests FGL2 prothrombinase presents a potential therapeutic target for clinical treatment of PH. NEW & NOTEWORTHY This is the first study to demonstrate that fibrinogen-like protein 2 (FGL2) participates in the pathological progression of pulmonary hypertension (PH) in human idiopathic pulmonary arterial hypertension, a monocrotaline rat PH model, and a hypoxia mouse PH model. Genetic knockout of Fgl2 significantly limited the development of PH indicated by reduced in situ thrombosis, vascular remodeling, and endothelial dysfunction, and suppressed PAR1 (proteinase-activated receptor 1) signaling and overactivation of platelets on PH. These results suggest FGL2 presents a potential therapeutic target for clinical treatment of PH.

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Faculty Opinions recommendation of Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718026516.793479771 ◽

2013 ◽

Author(s):

Vinicio de Jesus Perez

Keyword(s):

Nitric Oxide ◽

Pulmonary Arterial Hypertension ◽

Endothelial Dysfunction ◽

Arterial Hypertension ◽

Nitric Oxide Deficiency ◽

Pulmonary Arterial

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Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series)

Pulmonary Circulation ◽

10.1177/2045893217752912 ◽

2017 ◽

Vol 8 (1) ◽

pp. 204589321775291 ◽

Cited By ~ 36

Author(s):

Benoît Ranchoux ◽

Lloyd D. Harvey ◽

Ramon J. Ayon ◽

Aleksandra Babicheva ◽

Sebastien Bonnet ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Endothelial Dysfunction ◽

Arterial Hypertension ◽

Molecular Mechanisms ◽

Right Heart Failure ◽

Vascular Pathology ◽

Mesenchymal Transition ◽

Conference Series ◽

Major Player ◽

Pulmonary Arterial

Endothelial dysfunction is a major player in the development and progression of vascular pathology in pulmonary arterial hypertension (PAH), a disease associated with small vessel loss and obstructive vasculopathy that leads to increased pulmonary vascular resistance, subsequent right heart failure, and premature death. Over the past ten years, there has been tremendous progress in our understanding of pulmonary endothelial biology as it pertains to the genetic and molecular mechanisms that orchestrate the endothelial response to direct or indirect injury, and how their dysregulation can contribute to the pathogenesis of PAH. As one of the major topics included in the 2017 Grover Conference Series, discussion centered on recent developments in four areas of pulmonary endothelial biology: (1) angiogenesis; (2) endothelial-mesenchymal transition (EndMT); (3) epigenetics; and (4) biology of voltage-gated ion channels. The present review will summarize the content of these discussions and provide a perspective on the most promising aspects of endothelial dysfunction that may be amenable for therapeutic development.

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Intrauterine growth restriction and risk for arterial hypertension: a causal relationship?

Journal of Perinatal Medicine ◽

10.1515/jpm.2007.082 ◽

2007 ◽

Vol 35 (5) ◽

Cited By ~ 10

Author(s):

Ludwig Gortner

Keyword(s):

Arterial Hypertension ◽

Causal Relationship ◽

Intrauterine Growth Restriction ◽

Growth Restriction ◽

Intrauterine Growth

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Pulmonary arterial hypertension in systemic sclerosis: Diagnosis and treatment according to the European Society of Cardiology and European Respiratory Society 2015 guidelines

Journal of Scleroderma and Related Disorders ◽

10.1177/2397198318808998 ◽

2018 ◽

Vol 4 (1) ◽

pp. 35-42 ◽

Cited By ~ 4

Author(s):

Nicola Giordano ◽

Claudio Corallo ◽

Chiara Chirico ◽

Angelica Brazzi ◽

Adriana Marinetti ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Endothelial Dysfunction ◽

Arterial Hypertension ◽

Correct Diagnosis ◽

European Respiratory Society ◽

Long Term Outcome ◽

Screening Programs ◽

Pulmonary Arterial

Scleroderma (systemic sclerosis) is an autoimmune connective tissue disease which presents endothelial dysfunction and fibroblast dysregulation, resulting in vascular and fibrotic disorders. Pulmonary hypertension is frequent in patients with systemic sclerosis: the natural evolution of the disease can induce the development of different forms of pulmonary hypertension, representing one of the main causes of death. Among the different forms of pulmonary hypertension in systemic sclerosis, pulmonary arterial hypertension is the most frequent one (rate of occurrence is estimated between 7% and 12%). This pulmonary vascular complication should be treated with a combination of drugs that is able to counteract endothelial dysfunction, antagonizing the endothelin-1 system and replacing prostaglandin I2 and nitric oxide activity. A correct diagnosis is mandatory, because it is possible only for pulmonary arterial hypertension to use specific drugs that are able to control the symptomatic condition and the evolution of the disease. According to the most recent guidelines, for the patients with systemic sclerosis, also without pulmonary hypertension symptoms, echocardiography screening for the detection of pulmonary hypertension is recommended. Pulmonary arterial hypertension screening programs in systemic sclerosis patients is able to identify milder forms of the disease, allowing earlier management and better long-term outcome.

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