Computational modeling of angiogenesis: from matrix invasion to lumen formation
- dinsdag 22 december 2015
2311 GJ Leiden
Promotor(s): Prof. dr. R.M.H. Merks
In this thesis computational modeling is used to study key steps in the formation of capillaries. The sprouting of capillaries from existing blood vessels, a process called angiogenesis, is important in physiological processes such as embryogenesis and wound healing, and in pathological conditions such as tumor growth. Computational modeling of angiogenesis can help to unravel the mechanisms that drive blood vessel formation to help develop new therapies or to improve blood vessel growth in engineered tissues.
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 dissolve the so called plasminogen system, which dissolves fibrin matrices. A next model asks how endothelial cells can dynamically switch position during the formation of new sprouts. 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.
Inès van Arkel, Adviseur wetenschapscommunicatie
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