Universiteit Leiden

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Computational modeling of angiogenesis : from matrix invasion to lumen formation

Promotor: Roeland M.H. Merks

S.E.M. Boas
22 december 2015
Thesis in Leiden Repository

In this thesis computational modeling is used to help unravel the mechanisms of key steps in angiogenesis, the formation of new capillaries from existing blood vessels. The first step in angiogenesis is the invasion of new branches into the surrounding tissue by degradation of extracellular matrix proteins, e.g. fibrin. A first model describes how invading sprouts use the so called plasminogen system, which dissolves fibrin matrices. A next model asks how endothelial cells can dynamically switch position during angiogenesis. Based on experimental observations, several authors suggest that dynamic cell shuffling is under strict, genetic control. Our simulations show, however, that shuffling can emerge as a side effect of sprouting. Once a sprout is formed, it needs to hollow to allow blood flow. The mechanisms responsible for this hollowing, or lumen formation, are debated: vacuoles may punch a hole through the cell, or cells might repulse one another. In our simulations, both these hypotheses can work synergistically in lumen formation, suggesting that both hypotheses might work together. In a final chapter, we introduce a workflow to simultaneously test the impact of changes in the value of multiple parameters on the outcome of the type of models used in this thesis.