Abstract
Angiogenesis, the recruitment of new blood vessels, is a critical process for the growth, expansion, and metastatic dissemination of developing tumors. Three types of cells make up the new vasculature: tip cells, which migrate in response to gradients of vascular endothelial growth factor (VEGF), stalk cells, which proliferate and extend the vessels, and phalanx cells, which are quiescent and support the sprout. In this study we examine the contribution of tip cell migration rate and stalk cell proliferation rate on the formation of new vasculature. We calculate several vascular metrics, such as the number of vascular bifurcations per unit volume, vascular segment length per unit volume, and vascular tortuosity. These measurements predict that proliferation rate has a greater effect on the spread and extent of vascular growth compared to migration rate. Together, these findings provide strong implications for designing anti-angiogenic therapies that may differentially target endothelial cell proliferation and migration. Computational models can be used to predict optimal anti-angiogenic therapies in combination with other therapeutics to improve outcome.
Highlights
Modeling sprouting angiogenesis and for the prediction of potent anti-angiogenic treatments for reducing tumor size, inhibiting or slowing growth
These models help us understand the overall process of angiogenesis but in this study we are interested in the specific contributions of endothelial cell migration and proliferation
We find that the bifurcation density (BD) and the vascular length density (VLD) are mostly dependent on proliferation
Summary
Modeling sprouting angiogenesis and for the prediction of potent anti-angiogenic treatments for reducing tumor size, inhibiting or slowing growth. Computational models have examined the effects of interstitial and vessel pressure on drug delivery[22], transport of different drugs on tumor treatment[23], delivery of anti-angiogenic drugs on tumor growth[24], as well as examining the role of vasculature and drug delivery on drug resistance[25] These models help us understand the overall process of angiogenesis but in this study we are interested in the specific contributions of endothelial cell migration and proliferation. In a cellular Potts model, migration and growth were considered to be modulated by blood flow, without which the vasculature would collapse[28]; the model did not examine the individual contributions of endothelial cell elongation, proliferation and migration Popel and his colleagues in a series of studies[29,30] have formulated a class of 3D models of angiogenesis at multiple scales. The results of this study could provide guidance to pro-angiogenic therapeutic treatments
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