An integrative mathematical approach to understand how intraplaque angiogenesis and vascular structure impact atherosclerosis and their potential as n

An integrative mathematical approach to understand how intraplaque angiogenesis and vascular structure impact atherosclerosis and their potential as novel therapeutic targets

A recent fact sheet published by the British Heart Foundation (April 2023) outlines the alarming impact of cardiovascular diseases, which affect 7.6 million people in the UK and account for more than 160,000 deaths each year. Atherosclerosis, a leading contributor to cardiovascular disease, is marked by plaque build-up in large and medium-sized arteries.

In advanced stages, new blood vessels form within the vessel wall through a process known as neovascularisation. Accumulating genetic and clinical evidence supports that intra-plaque angiogenesis promotes atherosclerosis and leads to plaque destabilisation, rupture and erosion. However, the extent to which microvascular integrity and structure change during plaque development-and the consequences of such changes for immune cell infiltration, plaque composition and stability-remain unclear.

Answering these questions through advanced model simulations may ultimately lead to the identification and experimental testing of new mechanisms and targets for therapeutics within atherosclerosis.

The primary aim of this multidisciplinary project is to develop mechanistic mathematical models to understand how intra-plaque angiogenesis and vascular remodelling impact the progression and stability of human atherosclerotic plaques. A secondary project aim is to use the model to explore the potential for targeting angiogenesis and vascular remodelling to treat atherosclerosis.

Early work will focus on developing a mathematical model that couples intra-plaque angiogenesis and vascular remodelling with plaque growth, which will extend existing models of angiogenesis and early plaque growth. Through extensive parameter sensitivity analyses, we will use the model to investigate how structural features of the microvasculature impact oxygen levels within atherosclerotic lesions, their infiltration by immune cells and lipid, and, hence, the dynamics of their subsequent growth, composition and stability.

We will also develop additional models of relevant subcellular signalling pathways to understand how endothelial cell behaviours change in response to microenvironmental cues. By combining these subcellular models with the model of vascular plaque growth, we will assess the potential for manipulating intra-plaque angiogenesis by targeting signalling pathways within endothelial cells to treat atherosclerosis.

This project will be carried out in collaboration with Novo Nordisk (NN) and the mathematical models will be informed by, and tested in, tailored lab experiments using existing human in vitro endothelial and smooth muscle cell models within NN. The project will additionally involve collaboration with the Monaco Group for Cardiovascular Inflammation.

Both partnerships will enable mathematical insights to drive new experimental findings, benefiting both academia and industry in advancing cardiovascular therapeutic strategies.