Cellular and molecular mechanisms of resistance artery remodelling

Información del proyecto

Identificador del acuerdo de subvención: BMH4983069

Proyecto cerrado

Fecha de inicio 1 Abril 1998

Fecha de finalización 31 Marzo 2001

Financiado con arreglo a

• Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Coste total

Sin datos

Aportación de la UE

Sin datos

Coordinado por

UNIVERSITY OF AARHUS
Denmark

Objetivo

Objectives:
The aim of the project is to determine the processes which lead to abnormal structure of resistance vessels in hypertension. The project is based on the following hypotheses.
- That remodelling of resistance vessels can be initiated by the mechanical stress caused by transmural pressure, which in turn initiates growth processes similar to those initiated by growth factors such as PDGF.
- That the remodelling process is associated with the expression of the extracellular matrix (ECM) proteins fibronectin, thrombospondin, tenascin, and laminin, as well as decreased expression of heparan sulphate proteoglycans.
- That eutrophic remodelling (remodelling without net growth) can be initiated following activation with noradrenaline, but hypertrophic remodelling with angiotensin II.
- That eutrophic remodelling is due to a combination of integrin-mediated redistribution of existing material, as well as synthesis and apoptosis.

A major factor in long term cardiovascular homeostasis is how the vasculature structure adapts (remodels) in response to pressure, flow, and hormonal activation. Development of drugs for treatment of diseases involving changesin vascular structure (hypertension, heart failure) depends crucially on understanding these mechanisms. A previous project (EURAD) organized by the present applicant under BIOMED-I has demonstrated that in essential hypertension the vessels responsible for determining blood pressure (resistance vessels, e.g. small arteries and arterioles) are subject to 'eutrophic remodelling', a rearrangement of material. In contrast, we demonstrated hypertrophy (increase in vessel volume) in resistance vessels of patients with certain forms of secondary hypertension. Furthermore, it was shown that some, but not all, forms of antihypertensive treatment are able to reverse the remodelling. However, although these changes are now well defined, and despite their obvious clinical relevance, the molecular and cellular mechanisms behind the process are not understood. Possible causes of the remodelling process are the stress in the vascular wall and the hormonal environment. Current attempts to understand the process are based on in vivo studies with animal models, and on clinical studies. However, such studies only give indirect information about the mechanisms.

Questions to be answered include: does eutrophic remodelling involves rearrangement of wall material, or a combination of synthesis (proliferation) and apoptosis (programmed cell death); is there a fundamental difference between eutrophic and hypertrophic remodelling, or are both processes the result of the vasculature adapting to the current intravascular pressure and flow? As part of an international effort to answer these questions and understand the remodelling mechanisms, the present project, involving 5 laboratories and 2SMEs based in part on EURAD, will develop an in vitro model to allow the remodelling process to be studied in resistance vessels under controlled conditions. Here, isolated resistance vessels will be cannulated and held under known conditions of pressure and flow, and in a known hormonal environment. Using molecular, biochemical, and image analysis methods, we will use the in vitro system to determine the effect of pressure, flow and hormonal activation on vascular structure, and expression and distribution of mRNA and protein. The in vitro work will be based on hypotheses generated from in vivo studies, while further findings of the in vitro studies will then be tested in vivo, both in animals models and clinically. The laboratories participating in this project have a proven ability to collaborate with each other, and each provides a unique and crucial input. The results of this project will provide major new insights into the mechanisms by which the structure of the vasculature remodels in response to changes in its mechanical and hormonal environment.01 01

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias médicas y de la salud › medicina clínica › cardiología
• ciencias médicas y de la salud › medicina básica › fisiología › homeostasis

Programa(s)

• FP4-BIOMED 2 - Specific research, technological development and demonstration programme in the field of biomedicine and health, 1994-1998

Tema(s)

• 4.3.1 - Pathophysiology and basic mechanisms

Convocatoria de propuestas

Datos no disponibles

Régimen de financiación

CON - Coordination of research actions

Coordinador

UNIVERSITY OF AARHUS

• Aportación de la UE: Sin datos
• Dirección: 240,Wilhelm Meyers Allee University Park 240 ; 8000 AARHUS C ; Dinamarca
• Coste total: Sin datos