Tipping the Balance: Robustness of Tip Cell Selection, Migration and Fusion in Angiogenesis Export

@article{citeulike:6055631, 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, \^{a}€˜stabilised\^{a}€™ 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.}, author = {Bentley, Katie and Mariggi, Giovanni and Gerhardt, Holger and Bates, Paul A.}, citeulike-article-id = {6055631}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pcbi.1000549}, day = {30}, doi = {10.1371/journal.pcbi.1000549}, journal = {PLoS Comput Biol}, keywords = {computational\_biology, tip\_cell}, month = {October}, number = {10}, pages = {e1000549+}, posted-at = {2009-11-02 08:58:13}, priority = {2}, publisher = {Public Library of Science}, title = {Tipping the Balance: Robustness of Tip Cell Selection, Migration and Fusion in Angiogenesis}, url = {http://dx.doi.org/10.1371/journal.pcbi.1000549}, volume = {5}, year = {2009} }

TY - JOUR ID - citeulike:6055631 L3 - citeulike-article-id:6055631 N2 - 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. IS - 10 JF - PLoS Comput Biol TI - Tipping the Balance: Robustness of Tip Cell Selection, Migration and Fusion in Angiogenesis PB - Public Library of Science VL - 5 SP - e1000549 KW - computational_biology KW - tip_cell AU - Bentley, Katie AU - Mariggi, Giovanni AU - Gerhardt, Holger AU - Bates, Paul PY - 2009/10/30/ UR - http://dx.doi.org/10.1371/journal.pcbi.1000549 ER -