Hypoxia Impairs Systemic Endothelial Function in Individuals Prone to High-Altitude Pulmonary Edema

Berger, Marc Moritz; Hesse, Christiane; Dehnert, Christoph; Siedler, Heike; Kleinbongard, Petra; Bardenheuer, Hubert J.; Kelm, Malte; Bärtsch, Peter; Haefeli, Walter E.

doi:10.1164/rccm.200504-654oc

Cited by 136 publications

(131 citation statements)

References 30 publications

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“…VEGF-A acts on both BECs and LECs and uniquely regulates inter-LEC adherence through VE-cadherin and proliferative responses. In fact, acute hypoxia, which is a fundamental finding in HPS patients, induces VEGF-A production, and VEGF-A further induces the production of the hypoxia responsive transcription factor HIF1␣, forming an amplification loop (23,43,50,77) that causes high-altitude-induced edema (6,23,77). Although LEC responses of VEGFR2/VEGFR3 complexes are poorly understood (9,10,33,44), our findings indicate that ANDV-infected LECs uniquely respond to VEGF-A and that this response is regulated by VEGF-C.…”

Section: Discussionmentioning

confidence: 99%

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Andes Virus Infection of Lymphatic Endothelial Cells Causes Giant Cell and Enhanced Permeability Responses That Are Rapamycin and Vascular Endothelial Growth Factor C Sensitive

Gavrilovskaya

Gorbunova

Mackow

2012

J Virol

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Hantaviruses primarily infect endothelial cells (ECs) and nonlytically cause vascular changes that result in hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). Acute pulmonary edema during HPS may be caused by capillary leakage and failure of lymphatic vessels to clear fluids. Uniquely regulated lymphatic ECs (LECs) control fluid clearance, although roles for lymphatics in hantavirus disease remain undetermined. Here we report that hantaviruses productively infect LECs and that LEC infection by HPS causing Andes virus (ANDV) and HFRS causing Hantaan virus (HTNV) are inhibited by αvβ3integrin antibodies. Although αvβ3integrins regulate permeabilizing responses directed by vascular endothelial growth factor receptor 2 (VEGFR2), we found that only ANDV-infected LECs were hyperpermeabilized by the addition of VEGF-A. However, VEGF-C activation of LEC-specific VEGFR3 receptors blocked ANDV- and VEGF-A-induced LEC permeability. In addition, ∼75% of ANDV-infected LECs became viable mononuclear giant cells, >4 times larger than normal, in response to VEGF-A. Giant cells are associated with constitutive mammalian target of rapamycin (mTOR) activation, and we found that both giant LECs and LEC permeability were sensitive to rapamycin, an mTOR inhibitor, and VEGF-C addition. These findings indicate that ANDV uniquely alters VEGFR2-mTOR signaling responses of LECs, resulting in giant cell and LEC permeability responses. This suggests that ANDV infection alters normal LEC and lymphatic vessel functions which may contribute to edematous fluid accumulation during HPS. Moreover, the ability of VEGF-C and rapamycin to normalize LEC responses suggests a potential therapeutic approach for reducing pulmonary edema and the severity of HPS following ANDV infection.

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Section: Discussionmentioning

confidence: 99%

“…VEGF-A is induced by hypoxia and causes high-altitude-induced pulmonary edema (6,19,23,58,77). VEGF-A induces the dissociation of VE-cadherin from interendothelial adherens junctions via a VEGFR2-Src-VE-cadherin signaling pathway and thereby regulates the primary fluid barrier of the endothelium (19,24,25,49).…”

mentioning

confidence: 99%

Andes Virus Infection of Lymphatic Endothelial Cells Causes Giant Cell and Enhanced Permeability Responses That Are Rapamycin and Vascular Endothelial Growth Factor C Sensitive

Gavrilovskaya

Gorbunova

Mackow

2012

J Virol

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“…Endothelin production is greater in HAPE susceptibility [73], while lung NO production is reduced [56,74,75]. Systemic vascular endothelial NO generation is reduced more in hypoxic HAPE-susceptible subjects compared to controls [76]. This is probably also the case for the pulmonary circulation, as the above-cited measurements of exhaled NO and metabolites of NO in lavage fluid suggest.…”

Section: Haemodynamicsmentioning

confidence: 99%

Acute high-altitude sickness

2017

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At any point 1-5 days following ascent to altitudes ⩾2500 m, individuals are at risk of developing one of three forms of acute altitude illness: acute mountain sickness, a syndrome of nonspecific symptoms including headache, lassitude, dizziness and nausea; high-altitude cerebral oedema, a potentially fatal illness characterised by ataxia, decreased consciousness and characteristic changes on magnetic resonance imaging; and high-altitude pulmonary oedema, a noncardiogenic form of pulmonary oedema resulting from excessive hypoxic pulmonary vasoconstriction which can be fatal if not recognised and treated promptly. This review provides detailed information about each of these important clinical entities. After reviewing the clinical features, epidemiology and current understanding of the pathophysiology of each disorder, we describe the current pharmacological and nonpharmacological approaches to the prevention and treatment of these diseases.

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“…A layer of platelets on the surfaces of endothelial cells may also alter capillary permeability by affecting gas exchange within vast pulmonary capillary beds and thereby contribute to a hypoxic state (4,16,57). Hantavirus patients are hypoxic, and high-altitude-induced pulmonary edema results from hypoxic conditions inducing VEGF (4,16,31,47).…”

Section: Fig 3 Platelets Adhere To Pathogenic-hantavirus-infected Ementioning

confidence: 99%

“…Hantavirus patients are hypoxic, and high-altitude-induced pulmonary edema results from hypoxic conditions inducing VEGF (4,16,31,47). Since hypoxia-induced factor 1␣ (HIF1␣) induces VEGF and VEGF induces transcription of HIF1␣, an autocrine loop which amplifies endothelial cell permeability in response to hypoxia is formed (16,47,57,59).…”

Section: Fig 3 Platelets Adhere To Pathogenic-hantavirus-infected Ementioning

confidence: 99%

Pathogenic Hantaviruses Direct the Adherence of Quiescent Platelets to Infected Endothelial Cells

Gavrilovskaya

Gorbunova

Mackow

2010

J Virol

108

159

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Hantavirus infections are noted for their ability to infect endothelial cells, cause acute thrombocytopenia, and trigger 2 vascular-permeability-based diseases. However, hantavirus infections are not lytic, and the mechanisms by which hantaviruses cause capillary permeability and thrombocytopenia are only partially understood. The role of ␤ 3 integrins in hemostasis and the inactivation of ␤ 3 integrin receptors by pathogenic hantaviruses suggest the involvement of hantaviruses in altered platelet and endothelial cell functions that regulate permeability. Here, we determined that pathogenic hantaviruses bind to quiescent platelets via a ␤ 3 integrin-dependent mechanism. This suggests that platelets may contribute to hantavirus dissemination within infected patients and provides a means by which hantavirus binding to ␤ 3 integrin receptors prevents platelet activation. The ability of hantaviruses to bind platelets further suggested that cell-associated hantaviruses might recruit platelets to the endothelial cell surface.

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Hypoxia Impairs Systemic Endothelial Function in Individuals Prone to High-Altitude Pulmonary Edema

Abstract: Hypoxia markedly impairs vascular endothelial function in the systemic circulation in HAPE-S subjects due to a decreased bioavailability of NO. Impairment of the NO pathway could contribute to the enhanced hypoxic pulmonary vasoconstriction that is central to the pathogenesis of HAPE.

Cited by 136 publications

References 30 publications

Andes Virus Infection of Lymphatic Endothelial Cells Causes Giant Cell and Enhanced Permeability Responses That Are Rapamycin and Vascular Endothelial Growth Factor C Sensitive

Andes Virus Infection of Lymphatic Endothelial Cells Causes Giant Cell and Enhanced Permeability Responses That Are Rapamycin and Vascular Endothelial Growth Factor C Sensitive

Acute high-altitude sickness

Pathogenic Hantaviruses Direct the Adherence of Quiescent Platelets to Infected Endothelial Cells

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