Microvascular endothelial responses in critical illness: Focus on the Ang/Tie2 system

Rianne Mariëlle Jongman

Microvascular endothelial responses in critical illness: Focus on the Ang/Tie2 system

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Kritisch zieke patiënten worden op de intensive care behandeld, soms omdat een of meer vitale organen niet goed functioneren. Bij deze patiënten is de bloeddoorstroming in de kleinste bloedvaatjes, de haarvaatjes, verstoord. De organen zijn dan ‘lek’ en ontstoken wat kan leiden tot vochtophoping in organen en het uittreden van ontstekingscellen, waardoor organen kunnen gaan falen. Het doel van het onderzoek dat is beschreven in dit proefschrift was om te onderzoeken hoe bloedvatwandcellen zich gedragen in kritisch zieke patiënten en in muizen- en cel modellen die kritisch ziekte nabootsen. De balans van het Ang/Tie2 receptor systeem, het systeem dat regelt dat goed functionerende haarvaatjes niet lekken en niet ontstoken zijn, is verstoord in het bloed van patiënten die een openhartoperatie hebben ondergaan. Deze verstoring is groter wanneer deze patiënten na hun operatie nierfalen ontwikkelen. Verder hebben we beschreven dat het Ang/Tie2 systeem is verstoord in nieren van patiënten met septische shock die zijn overleden met nierfalen. We hebben gevonden dat de verstoorde balans van het Ang/Tie2 systeem komt door verstoring in de bloeddoorstroming in de haarvaatjes in organen. In muizenmodellen waarin de verstoorde balans in kritische ziekte van het Ang/Tie2 systeem door middel van genetische manipulatie is nagebootst, hebben we laten zien dat bloedvatwandcellen zich niet heel anders gedragen wanneer Tie2 verminderd wordt aangemaakt. Vervolgonderzoek zal zich erop richten de onderliggende mechanismen van bloedvatwandcellen en de rol van het Ang/Tie2 systeem in kritisch zieke patiënten en in modellen hiervan, verder te ontrafelen.

Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Molema, Ingrid, Supervisor Zijlstra, Jan, Supervisor Struys, Michel, Supervisor van Meurs, Matijs, Co-supervisor
Datum van toekenning	1-nov-2017
Plaats van publicatie	[Groningen]
Uitgever	Rijksuniversiteit Groningen
Gedrukte ISBN's	978-94-034-0104-1
Elektronische ISBN's	978-94-034-0103-4
Status	Published - 2017

Toegang tot document

Title and contentsFinal publisher's version, 116 KB
Chapter 1Final publisher's version, 2,32 MB
Chapter 2Final publisher's version, 716 KB
Chapter 3Final publisher's version, 3,98 MB
Chapter 4Final publisher's version, 1,58 MB
Chapter 5Final publisher's version, 1,46 MB
Chapter 6Final publisher's version, 13,6 MB
Chapter 7Final publisher's version, 1,39 MB
AppendicesFinal publisher's version, 1,13 MB
Complete thesisFinal publisher's version, 22,6 MB
PropositionsFinal publisher's version, 25,4 KB

Citeer dit

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title = "Microvascular endothelial responses in critical illness: Focus on the Ang/Tie2 system",

abstract = "Critically ill patients in the Intensive Care unit need medical care, because of failure of one or more organs. These patients suffer from systemic low blood pressure, caused by alterations in blood flow in the smallest blood vessels. As a consequence the organs are {\textquoteleft}leaky{\textquoteright}, leading to edema formation. This can result in organ failure or even death. The cause for these leaky blood vessels in critically ill patients is not known. The aim of the research described in this thesis was to study the behavior of the endothelial cells in blood vessel wall of critically ill patients and in models thereof. We showed that in blood of patients who underwent cardiac surgery the balance of the molecules of the Angiopoietin/Tie2 system, the system that regulates the integrity of blood vessels, is disturbed. This balance in soluble Ang/Tie2 molecules is more deranged in these patients who developed kidney failure after cardiac surgery. Furthermore, in kidneys of patients who died of sepsis-induced acute kidney injury, the Tie2 production is diminished. In cell models, we demonstrated that this loss of Tie2 can be a result of a decrease in shear stress which reflects a reduction in blood flow in vivo. In mouse models mimicking critical illness, the inflammatory responses of the endothelium are not changed when the expression of Tie2 is halved by genetic manipulation. Future research will focus on unraveling the underlying mechanisms of the endothelial Ang/Tie2 system in blood vessels in critical illness.",

author = "Jongman, {Rianne Mari{\"e}lle}",

year = "2017",

language = "English",

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publisher = "Rijksuniversiteit Groningen",

school = "University of Groningen",

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TY - THES

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T2 - Focus on the Ang/Tie2 system

AU - Jongman, Rianne Mariëlle

PY - 2017

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N2 - Critically ill patients in the Intensive Care unit need medical care, because of failure of one or more organs. These patients suffer from systemic low blood pressure, caused by alterations in blood flow in the smallest blood vessels. As a consequence the organs are ‘leaky’, leading to edema formation. This can result in organ failure or even death. The cause for these leaky blood vessels in critically ill patients is not known. The aim of the research described in this thesis was to study the behavior of the endothelial cells in blood vessel wall of critically ill patients and in models thereof. We showed that in blood of patients who underwent cardiac surgery the balance of the molecules of the Angiopoietin/Tie2 system, the system that regulates the integrity of blood vessels, is disturbed. This balance in soluble Ang/Tie2 molecules is more deranged in these patients who developed kidney failure after cardiac surgery. Furthermore, in kidneys of patients who died of sepsis-induced acute kidney injury, the Tie2 production is diminished. In cell models, we demonstrated that this loss of Tie2 can be a result of a decrease in shear stress which reflects a reduction in blood flow in vivo. In mouse models mimicking critical illness, the inflammatory responses of the endothelium are not changed when the expression of Tie2 is halved by genetic manipulation. Future research will focus on unraveling the underlying mechanisms of the endothelial Ang/Tie2 system in blood vessels in critical illness.

AB - Critically ill patients in the Intensive Care unit need medical care, because of failure of one or more organs. These patients suffer from systemic low blood pressure, caused by alterations in blood flow in the smallest blood vessels. As a consequence the organs are ‘leaky’, leading to edema formation. This can result in organ failure or even death. The cause for these leaky blood vessels in critically ill patients is not known. The aim of the research described in this thesis was to study the behavior of the endothelial cells in blood vessel wall of critically ill patients and in models thereof. We showed that in blood of patients who underwent cardiac surgery the balance of the molecules of the Angiopoietin/Tie2 system, the system that regulates the integrity of blood vessels, is disturbed. This balance in soluble Ang/Tie2 molecules is more deranged in these patients who developed kidney failure after cardiac surgery. Furthermore, in kidneys of patients who died of sepsis-induced acute kidney injury, the Tie2 production is diminished. In cell models, we demonstrated that this loss of Tie2 can be a result of a decrease in shear stress which reflects a reduction in blood flow in vivo. In mouse models mimicking critical illness, the inflammatory responses of the endothelium are not changed when the expression of Tie2 is halved by genetic manipulation. Future research will focus on unraveling the underlying mechanisms of the endothelial Ang/Tie2 system in blood vessels in critical illness.

M3 - Thesis fully internal (DIV)

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PB - Rijksuniversiteit Groningen

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