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Studies on extracellular matrix proteins in vascular disease

Ström, Åsa LU (2004)
Abstract (Swedish)
Popular Abstract in Swedish

Det är känt sedan tidigare att komponenter från blodkärlets bindväv på olika sätt kan påverka sjukdomstillstånd som uppkommer i kärlväggen. En av dessa sjukdomar är ateroskleros (åderförkalkning), som genom sina följdsjukdomar (hjärtinfarkt, kärlkramp, stroke mm) utgör den vanligaste dödsorsaken i västvärlden. I den här avhandlingen studeras hur komponenter av kärlväggens bindväv kan påverka utvecklingen av ateroskleros. Blodkärlsväggen består till största delen av en specialiserad celltyp, den glatta muskelcellen. Då kärlet utsätts för en skada, såsom vid ateroskleros, vandrar glatta muskelceller ut till kärlets innersta lager, intiman, för att reparera skadan, där de delar på sig och utsöndrar... (More)
Popular Abstract in Swedish

Det är känt sedan tidigare att komponenter från blodkärlets bindväv på olika sätt kan påverka sjukdomstillstånd som uppkommer i kärlväggen. En av dessa sjukdomar är ateroskleros (åderförkalkning), som genom sina följdsjukdomar (hjärtinfarkt, kärlkramp, stroke mm) utgör den vanligaste dödsorsaken i västvärlden. I den här avhandlingen studeras hur komponenter av kärlväggens bindväv kan påverka utvecklingen av ateroskleros. Blodkärlsväggen består till största delen av en specialiserad celltyp, den glatta muskelcellen. Då kärlet utsätts för en skada, såsom vid ateroskleros, vandrar glatta muskelceller ut till kärlets innersta lager, intiman, för att reparera skadan, där de delar på sig och utsöndrar bindvävskomponenter. Denna reparationsprocess leder till en förtjockning av intiman, och utgör en av grundorsakerna till utveckling av ateroskleros. Reparationsprocessen leder också till att sammansättningen av bindväven i kärlväggen förändras, vilket kan påverka funktionen av de glatta muskelcellerna. I den här avhandlingen undersöker vi hur bindvävs-sammansättningen förändras i samband med en skada och hur detta påverkar utvecklingen av ateroskleros. Till vår hjälp, har vi använt oss av en genmodifierad mus som spontant utvecklar ateroskleros. Vi har även gjort experiment på glatta muskelceller odlade i cellskålar. Huvuddelen av studierna i den här avhandlingen behandlar bindvävsproteinet osteopontin. Resultaten visar att osteopontin är en av de komponenter i bindväven som förändras vid ateroskleros. Med hjälp av möss som saknar genen för osteopontin, har vi studerat hur detta protein påverkar sjukdomsutvecklingen. Vi har även undersökt hur osteopontin påverkar de glatta muskelcellernas funktioner. Experimenten visar bland annat att möss som saknar genen för osteopontin inte utvecklar ateroskleros i samma utsträckning som möss som har normalt genuttryck för osteopontin. (Less)
Abstract
The composition of the vascular extracellular matrix (ECM) is altered during remodeling conditions such as atherosclerosis. The changed ECM regulates events that are important for the progression of disease including smooth muscle cell (SMC) behaviour and collagen fiber formation. The overall aim of this project was to relate changes in the composition of ECM in the arterial wall to processes during atherosclerosis. The first part includes a characterisation of ECM components in atherosclerotic arteries of ApoE/LDLr double deficient mice. The second part involves functional studies on individual ECM components with focus on osteopontin (OPN) as well as on versican and fibulin-2. Experiments have been performed both in vivo in an... (More)
The composition of the vascular extracellular matrix (ECM) is altered during remodeling conditions such as atherosclerosis. The changed ECM regulates events that are important for the progression of disease including smooth muscle cell (SMC) behaviour and collagen fiber formation. The overall aim of this project was to relate changes in the composition of ECM in the arterial wall to processes during atherosclerosis. The first part includes a characterisation of ECM components in atherosclerotic arteries of ApoE/LDLr double deficient mice. The second part involves functional studies on individual ECM components with focus on osteopontin (OPN) as well as on versican and fibulin-2. Experiments have been performed both in vivo in an atherosclerotic mouse model and in vitro on cultured rat aortic smooth muscle cells (SMC). Paper I. This immunohistochemical study demonstrated presence of the cell and/or collagen binding ECM components OPN, COMP, decorin, PRELP and fibromodulin in atherosclerotic arteries of ApoE/LDLr deficient mice. Paper II. The importance of osteopontin during the atherosclerotic process was studied by crossing OPN deficient mice with ApoE/LDLr deficient mice (AL) generating a mouse which lacks expression of ApoE, LDLR and OPN (ALO). The results demonstrated that OPN deficiency reduced atherogenesis in atherosclerotic mice. Furthermore, the data indicated that OPN might be involved in the regulation of vascular remodeling, inflammation and lipid metabolism. Paper III. In an attempt to clarify the role of OPN during the atherosclerotic process, the effect of OPN on SMC functions was studied. Mutated forms of OPN were generated lacking two integrin binding sites and the cleavage site for thrombin. The effect of thrombin cleavage of OPN was also studied and cell culture experiments showed decreased adhesion of SMC to thrombin-cleaved OPN compared to intact OPN. Paper IV. The presence of versican and fibulin-2 was studied in atherosclerotic arteries of ApoE/LDLr deficient mice and in cultured SMC. Versican and fibulin-2 were present in lesions and fibulin-2 was upregulated in SMC during phenotypic modulation. Blocking the interaction between versican and fibulin-2 inhibited SMC migration. The results indicate that fibulin-2 is produced by SMC as a response to injury and participates in the ECM organisation during vessel wall repair. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Professor Boren, Jan, The Cardiovascular Institute, Göteborg University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Kardiovaskulära systemet, Cardiovascular system, smooth muscle cells, osteopontin, extracellular matrix, atherosclerosis
pages
110 pages
publisher
Åsa Ström, Section for Connective Tissue Biology, BMC, C12, 221 84 Lund,
defense location
BMC, Lund
defense date
2004-05-07 10:15
ISBN
91-628-5965-X
language
English
LU publication?
yes
id
a4ec7d9f-3a90-48d0-87e0-c09bc7681722 (old id 466872)
date added to LUP
2007-09-26 12:56:12
date last changed
2016-09-19 08:45:02
@phdthesis{a4ec7d9f-3a90-48d0-87e0-c09bc7681722,
  abstract     = {The composition of the vascular extracellular matrix (ECM) is altered during remodeling conditions such as atherosclerosis. The changed ECM regulates events that are important for the progression of disease including smooth muscle cell (SMC) behaviour and collagen fiber formation. The overall aim of this project was to relate changes in the composition of ECM in the arterial wall to processes during atherosclerosis. The first part includes a characterisation of ECM components in atherosclerotic arteries of ApoE/LDLr double deficient mice. The second part involves functional studies on individual ECM components with focus on osteopontin (OPN) as well as on versican and fibulin-2. Experiments have been performed both in vivo in an atherosclerotic mouse model and in vitro on cultured rat aortic smooth muscle cells (SMC). Paper I. This immunohistochemical study demonstrated presence of the cell and/or collagen binding ECM components OPN, COMP, decorin, PRELP and fibromodulin in atherosclerotic arteries of ApoE/LDLr deficient mice. Paper II. The importance of osteopontin during the atherosclerotic process was studied by crossing OPN deficient mice with ApoE/LDLr deficient mice (AL) generating a mouse which lacks expression of ApoE, LDLR and OPN (ALO). The results demonstrated that OPN deficiency reduced atherogenesis in atherosclerotic mice. Furthermore, the data indicated that OPN might be involved in the regulation of vascular remodeling, inflammation and lipid metabolism. Paper III. In an attempt to clarify the role of OPN during the atherosclerotic process, the effect of OPN on SMC functions was studied. Mutated forms of OPN were generated lacking two integrin binding sites and the cleavage site for thrombin. The effect of thrombin cleavage of OPN was also studied and cell culture experiments showed decreased adhesion of SMC to thrombin-cleaved OPN compared to intact OPN. Paper IV. The presence of versican and fibulin-2 was studied in atherosclerotic arteries of ApoE/LDLr deficient mice and in cultured SMC. Versican and fibulin-2 were present in lesions and fibulin-2 was upregulated in SMC during phenotypic modulation. Blocking the interaction between versican and fibulin-2 inhibited SMC migration. The results indicate that fibulin-2 is produced by SMC as a response to injury and participates in the ECM organisation during vessel wall repair.},
  author       = {Ström, Åsa},
  isbn         = {91-628-5965-X},
  keyword      = {Kardiovaskulära systemet,Cardiovascular system,smooth muscle cells,osteopontin,extracellular matrix,atherosclerosis},
  language     = {eng},
  pages        = {110},
  publisher    = {Åsa Ström, Section for Connective Tissue Biology, BMC, C12, 221 84 Lund,},
  school       = {Lund University},
  title        = {Studies on extracellular matrix proteins in vascular disease},
  year         = {2004},
}