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Abstract
Vascular abnormalities contribute to many diseases such as cancer and diabetic retinopathy. In angiogenesis new blood vessels, headed by a migrating tip cell, sprout from pre-existing vessels in response to signals, e.g., vascular endothelial growth factor (VEGF). Tip cells meet and fuse (anastomosis) to form blood-flow supporting loops. Tip cell selection is achieved by Dll4-Notch mediated lateral inhibition resulting, under normal conditions, in an interleaved arrangement of tip and non-migrating stalk cells. Previously, we showed that the increased VEGF levels found in many diseases can cause the delayed negative feedback of lateral inhibition to produce abnormal oscillations of tip/stalk cell fates. Here we describe the development and implementation of a novel physics-based hierarchical agent model, tightly coupled to in vivo data, to explore the system dynamics as perpetual lateral inhibition combines with tip cell migration and fusion. We explore the tipping point between normal and abnormal sprouting as VEGF increases. A novel filopodia-adhesion driven migration mechanism is presented and validated against in vivo data. Due to the unique feature of ongoing lateral inhibition, ‘stabilised’ tip/stalk cell patterns show sensitivity to the formation of new cell-cell junctions during fusion: we predict cell fates can reverse. The fusing tip cells become inhibited and neighbouring stalk cells flip fate, recursively providing new tip cells. Junction size emerges as a key factor in establishing a stable tip/stalk pattern. Cell-cell junctions elongate as tip cells migrate, which is shown to provide positive feedback to lateral inhibition, causing it to be more susceptible to pathological oscillations. Importantly, down-regulation of the migratory pathway alone is shown to be sufficient to rescue the sprouting system from oscillation and restore stability. Thus we suggest the use of migration inhibitors as therapeutic agents for vascular normalisation in cancer.
Highlights
Sprouting angiogenesis [1] is integral to a plethora of normal and pathological biological processes, such as embryonic development, wound healing and cancer
The signals are known to be different in disease and are thought to cause the process of angiogenesis to progress abnormally, though the reasons for this remain unclear
We focus on the behaviours of three inter-related initial angiogenic pathways associated with changes in tissue signal conditions, utilising both in silico and in vivo approaches
Summary
Sprouting angiogenesis [1] is integral to a plethora of normal and pathological biological processes, such as embryonic development, wound healing and cancer. A dense vascular network builds up, which is later pruned by remodelling processes related to flow [4]. Under pathological conditions, such as cancer and diabetic retinopathy, overly high VEGF concentrations are observed, resulting in aberrant sprouting and a tortuous, leaky network with poor perfusion [5,6]. Normalisation of blood vessel development in disease has important therapeutic potential. Our overall aim is to first use a systems approach to understand how changes in VEGF result in a switch between normal and abnormal tip cell selection, sprouting and fusion and predict methods to tip the balance back to normal angiogenesis in disease. We keep our parsimonious in silico model closely tied to quantitative in vivo angiogenesis imaging data throughout the paper; an approach recently highlighted as imperative for understanding complex developmental systems [8]
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