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Molecular and cellular mechanisms of arterial pathophysiology

Objective

To determine the molecular mechanisms controlling the expression of vascular endothelial growth factor by hypoxia and other growth factors.
To determine what factors induce smooth muscle cell migration in the arterial wall.
To examine the overexpression of 15 lipoxygenase, scavenger receptor, LDL receptor and inhibition of mevalonate metabolism in arterial intimal hyperplasia, in the presence and absence of hypercholesterolaemia.

Exposure of cultured rabbit vascular smooth muscle cells (VSMC) to hypoxia and multiple protein growth factors including platelet-derived growth factor (PDGF) induces an increase in expression of vascular endothelial growth factor (VEGF), an angiogenic factor and permeability-increasing factor for endothelial cells. It is proposed to extend previous observations by identifying other factors which induce VEGF expression in VSMC, to investigate the molecular mechanisms underlying these events and to identify the putative hypoxia inducible VSMC migration factor(s). Both the collared artery model and human arterial tissue will be used. The spatial and temporal changes in VSMC phenotype and the interaction with hypoxia and hypercholesterolaemia will be studied. An important aim will be to determine the expression in the collared artery of genes involved in cholesterol uptake and metabolism and implicated in atherogenesis in humans, including 15-lipoxygenase (15-LO) the low density lipoprotein (LDL) receptor and the scavenger receptor. The role of the biosynthetic mevalonate pathway in neointimal hyperplasia will be studied by examining the effects of inhibitors of both HMG-CoA reductase and of farnesyl transferase in normal and collared arteries. Interactions between hypoxia and the mevalonate and cholesterol pathways will also be investigated in VSMC and in VSMC lines stably expressing 15-LO, LDL-receptor and the scavenger receptor. A major goal of the proposed work is to develop effective strategies for gene transfer into the collared artery.

Funding Scheme

CSC - Cost-sharing contracts

Coordinator

University College London
Address
140 Tottenham Court Road
W1P 9NL London
United Kingdom

Participants (3)

Max-Planck-Gesellschaft zur Förderungder Wissenschaften e.V.
Germany
Address
Parkstraße 1
61231 Bad Nauheim
THE UNIVERSITY OF MILANO
Italy
Address
Via Balzaretti 9
20133 Milano
UNIVERSITY OF KUOPIO
Finland
Address
2,Neulaniementie 2
70211 Kuopio