Systems-Mechanobiology of Endothelial Gap Dynamics

The vasculature is a complex system, critical to the functioning of higher-level organisms. It is composed of large vessels that branch into smaller and smaller vessels. On the smallest scale, the microvasculature consists of arterioles, venules and capillaries.

Here, oxygen and nutrients are exchanged between the vessels and the tissue. Also, immune or cancer cells can transmigrate through gaps within the blood vessels into the surrounding tissues. For the immune system, this is a critical function, as immune cells need to reach sites of infection.

However, high levels of transmigration may also contribute to chronic inflammation, and cancer cells transmigrate the blood vessels during metastasis. Therefore, a tight regulation of the blood vessel gaps is critical during homeostasis, and de-regulation of gaps may contribute to diseases.

Our preliminary mathematical modelling/in vitro experimental work revealed that a balance of intracellular forces in the endothelial cells, the cells that line the blood vessels, regulates the formation of gaps in between the cells. We found that these gaps occur most frequently at the vertex points between three endothelial cells, and may appear autonomously, in absence of transmigrating cells.

This finding complemented earlier studies that uncovered a critical role of inflammatory signals, released by transmigrating cells, in the regulation of endothelial cells. We further showed that transmigrating cells may exploit these autonomously forming gaps by migrating towards the gaps, where they cross the endothelium. Therefore, studying the dynamic nature of the endothelium, and the resulting formation of gaps, is critical to understand the physiologically important processes of immune and cancer transmigration.

In vivo, the dynamics of the microvasculature is influenced by several further biophysical properties not present in most in vitro assays. Notably, blood flow in the vessels, interactions of endothelial cells with the surrounding extracellular matrix, and the complex geometry and topology of the microvasculature, have all been found to influence endothelial dynamics individually.

In vivo these properties exist simultaneously. Systems biology models are typically employed to study cellular decision making in response to multiple stimuli. However, current systems biology models are focused on the study of multiple molecular stimuli, e.g. inflammatory cytokines, but cannot capture biophysical stimuli.

Therefore, there is an urgent need to incorporate the effect of multiple biophysical stimuli into systems biology models.

In this project, we are developing an integrative modelling/experimental approach that incorporates multiple physiological biophysical properties into both mathematical models and in vitro assays. Our approach will advance models and experiments iteratively together to gain unprecedented insights into the dynamic nature of the endothelial microvasculature.

The outcome will be a versatile mathematical modelling platform to study the dynamics of the microvasculature in homeostasis, and will underpin future work on the contribution of endothelial dynamics to diseases. Moreover, we will advance our recently developed engineered in vitro assays that can generate stable, perfused 3D microvasculature in complex extracellular matrices, and that is therefore ideally suited to validate our mathematical modelling predictions.

The combined modelling/experimental system will be used to test several specific biological hypotheses on the complex role of major contributors to endothelial dynamics and gap formation.