Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress

Jerkić, Mirjana; Kabir, M. Golam; Davies, Adrienne; Yu, Lisa; McIntyre, Brendan A.S.; Husain, Nasir W.; Enomoto, Masahiro; Sotov, Valentin; Husain, Mansoor; Henkelman, Mark; Belik, Jaques; Letarte, Michelle

doi:10.1093/cvr/cvr232

Cited by 70 publications

(61 citation statements)

References 37 publications

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“…BMP4 treatment of mouse aortaes led to impaired endothelium-dependent relaxations, exaggerated endothelium-dependent contractions via cyclooxygenase-2 (COX-2) upregulation in a reactive oxygen species (ROS) dependent manner [129]. It has been also reported that increased pulmonary vascular remodelling in Alk1+/− mice leads to signs of PAH and it has been shown that this is associated with eNOS-dependent ROS production and it can be averted by anti-oxidant treatment [130]. Interestingly prostacyclin analogues were shown to enhance BMP induced Smad1/5 phosphorylation by suppressing Smad6 expression [131].…”

Section: Vascular Tone and Tgf Signalingmentioning

confidence: 99%

TGFβ Signaling and Cardiovascular Diseases

Pardali¹,

Dijke²

2012

Int. J. Biol. Sci.

151

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Transforming growth factor  (TGF) family members are involved in a wide range of diverse functions and play key roles in embryogenesis, development and tissue homeostasis. Perturbation of TGF signaling may lead to vascular and other diseases. In vitro studies have provided evidence that TGF family members have a wide range of diverse effects on vascular cells, which are highly dependent on cellular context. Consistent with these observations genetic studies in mice and humans showed that TGF family members have ambiguous effects on the function of the cardiovascular system. In this review we discuss the recent advances on TGF signaling in (cardio)vascular diseases, and describe the value of TGF signaling as both a disease marker and therapeutic target for (cardio)vascular diseases.

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Section: Vascular Tone and Tgf Signalingmentioning

confidence: 99%

TGFβ Signaling and Cardiovascular Diseases

Pardali¹,

Dijke²

2012

Int. J. Biol. Sci.

151

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“…ROS may be involved in development of HPV and pulmonary hypertension due to diverse mechanisms, either by the above mentioned disruption in the NO-pathway, by interaction with the endothelial layer, or by uncoupling of oxidases, such as xanthine oxidase and nicotinamide adenine dinucleotide phosphate oxidase (Demarco et al, 2010 ;Jerkic et al, 2011 ;Lane et al, 2011). Because of their short half lives, quantification of ROS is difficult and requires special methodological settings.…”

Section: Oxidative Stress In Hypobaric Hypoxia and Influence On Vessementioning

confidence: 99%

Oxidative Stress in Hypobaric Hypoxia and Influence on Vessel-Tone Modifying Mediators

Hefti

Sonntag

Hefti

et al. 2013

High Altitude Medicine & Biology

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Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction. We hypothesized that increased hypoxemia is associated with an increase in vasoconstrictive mediators and decrease of vasodilatators leading to a vasoconstrictive net effect. Furthermore, we suggested oxidative stress being partly involved in changement of these parameters. Oxygen saturation (Sao2) and clinical parameters were assessed in 34 volunteers before and during a Swiss research expedition to Mount Muztagh Ata (7549 m) in Western China. Blood samples were taken at four different sites up to an altitude of 6865 m. A mass spectrometry-based targeted metabolomic platform was used to detect multiple parameters, and revealed functional impairment of enzymes that require oxidation-sensitive cofactors. Specifically, the tetrahydrobiopterin (BH4)-dependent enzyme nitric oxide synthase (NOS) showed significantly lower activities (citrulline-to-arginine ratio decreased from baseline median 0.21 to 0.14 at 6265 m), indicating lower NO availability resulting in less vasodilatative activity. Correspondingly, an increase in systemic oxidative stress was found with a significant increase of the percentage of methionine sulfoxide from a median 6% under normoxic condition to a median level of 30% (p<0.001) in camp 1 at 5533 m. Furthermore, significant increase in vasoconstrictive mediators (e.g., tryptophan, serotonin, and peroxidation-sensitive lipids) were found. During ascent up to 6865 m, significant altitude-dependent changes in multiple vessel-tone modifying mediators with excess in vasoconstrictive metabolites could be demonstrated. These changes, as well as highly significant increase in systemic oxidative stress, may be predictive for increase in acute mountain sickness score and changes in Sao2. 14:273-279, 2013.-Increased pulmonary artery pressure is a well-known phenomenon of hypoxia and is seen in patients with chronic pulmonary diseases, and also in mountaineers on high altitude expedition. Different mediators are known to regulate pulmonary artery vessel tone. However, exact mechanisms are not fully understood and a multimodal process consisting of a whole panel of mediators is supposed to cause pulmonary artery vasoconstriction. We hypothesized that increased hypoxemia is associated with an increase in vasoconstrictive mediators and decrease of vasodilatators leading to a vasoconstrictive net effect. Furthermore, we suggested oxidative stress being partly involved in changement of these parameters. Oxygen saturation (Sao 2 ) and clinical parameters were assessed in 34 volunteers before and during a Swiss research expedition to Mount Muztagh Ata (7549 m) in Western China. Bl...

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“…Mice with a heterozygous deletion of Alk1 have been found to develop PH associated with increased ROS production. The level of NO production is decreased, partially because of decreased production caused by eNOS uncoupling and partially because of a ROS-mediated reduction in NO bioavailability (53).…”

Section: Edno As a Paracrine Regulatormentioning

confidence: 99%

“…Such action is diminished in pulmonary hypertension, in part because of reduced production of NO by uncoupled endothelial nitric oxide synthase (eNOS) (34). The uncoupled eNOS generates superoxide anions, which reduce the bioavailability of NO (53). NO can counteract the vasoconstriction and vascular remodeling caused by ET-1 action through the stimulation of soluble guanylyl cyclase (sGC) and the elevation of cyclic guanosine monophosphate (cGMP).…”

Section: Edno As a Paracrine Regulatormentioning

confidence: 99%

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

Gao

Chen

Raj

2016

Am J Respir Cell Mol Biol

115

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In the pulmonary vasculature, the endothelial and smooth muscle cells are two key cell types that play a major role in the pathobiology of pulmonary vascular disease and pulmonary hypertension. The normal interactions between these two cell types are important for the homeostasis of the pulmonary circulation, and any aberrant interaction between them may lead to various disease states including pulmonary vascular remodeling and pulmonary hypertension. It is well recognized that the endothelial cell can regulate the function of the underlying smooth muscle cell by releasing various bioactive agents such as nitric oxide and endothelin-1. In addition to such paracrine regulation, other mechanisms exist by which there is cross-talk between these two cell types, including communication via the myoendothelial injunctions and information transfer via extracellular vesicles. Emerging evidence suggests that these nonparacrine mechanisms play an important role in the regulation of pulmonary vascular tone and the determination of cell phenotype and that they are critically involved in the pathobiology of pulmonary hypertension.Keywords: paracrine; myoendothelial injunction; microvesicles; vasoconstriction; vascular remodelingIn the pulmonary vasculature, endothelial cells (ECs) and smooth muscle cells (SMCs) are the key cell types involved in the regulation of vessel diameter in most of the pulmonary vascular tree and thereby they regulate pulmonary arterial pressure and total vascular resistance. ECs, which are strategically located as the innermost layer of the blood vessel and are in contact with the circulating blood, exert a delicate and constant influence on the underlying vascular smooth muscle cells (VSMCs). It is well recognized that the regulation of pulmonary vasoreactivity by the endothelium is predominantly accomplished by paracrine signaling through the release of various vasoactive agents such as nitric oxide (NO), endothelin-1 (ET-1) (1-3), and others (4-8). However, there is increasing evidence that the relationship between the EC and the SMC is not a simple one-way interaction from the endothelium to the SMC; rather, there are complicated interactions between them (9-11). Moreover, the communication patterns are not limited to paracrine signaling; cross-talk through myoendothelial gap junctions (MEJs), extracellular vesicles (EVs), and other mechanisms is critically involved (12)(13)(14)(15)(16)(17)(18)(19)(20). These mechanisms operate in a complicated but co-ordinated manner to maintain the homeostasis of the pulmonary circulation. Under pathological conditions, the interaction between ECs and VSMCs may be chronically altered so that a sustained increase in vasocontractility and abnormal vascular proliferation develops, which leads to high pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and the clinical condition, pulmonary hypertension (PH) (1,(21)(22)(23)(24). This article discusses the recent progress in our knowledge of the interactions between ECs and SMCs thr...

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Pulmonary hypertension in adult Alk1 heterozygous mice due to oxidative stress

Abstract: The increased pulmonary vascular remodelling in Alk1(+/-) mice leads to signs of PH and is associated with eNOS-dependent ROS production, which is preventable by anti-oxidant treatment.

Cited by 70 publications

References 37 publications

TGFβ Signaling and Cardiovascular Diseases

TGFβ Signaling and Cardiovascular Diseases

Oxidative Stress in Hypobaric Hypoxia and Influence on Vessel-Tone Modifying Mediators

Endothelial and Smooth Muscle Cell Interactions in the Pathobiology of Pulmonary Hypertension

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