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Sprouting is controlled by the balance between pro-angiogenic signals (+), like vascular endothelial growth factor (VEGF), and factors that stop movement (-), inhibitor Notch.
(Green) endothelial cells (ECs) sprouting , (Grey) ECs failing to sprout.
Image credit: Nature 2007
Blood vessels have newly found mechanical switches
For more than 40 years, research into the structure and function of cells that line blood vessels has sought to understand how blood vessels form and sometimes become diseased.
Vascular research is the focus of two recent papers coauthored by investigators in the Center for Vascular Biology Research (CVBR) at Beth Israel Deaconess Medical Center. One study provides a novel explanation for the enlarged blood vessels that are seen in various diseases, including tumors and retinopathies.
"Understanding how, when and why individual endothelial cells change shape in response to environmental signals is key to understanding normal and abnormal blood vessel growth. Such insight could prove valuable in the treatment of cancer, which relies on a constant blood supply to support tumor growth and spread."
Katie Bentley, PhD, assistant professor of pathology, Harvard Medical School, and Group Leader of the Computational Biology Laboratory in the Center for Vascular Biology Research.
Bentley's training is in Adaptive Systems research, an interdisciplinary field working to explain fundamental organizing principles of living systems using simulation, robotics and experimental models. Her work focuses on construction of simulated (Simulant) endothelial cells.
She explains. "[Using Simulants] We tinker with how to set up internal cell workings and then compare how our changes in models compares to real cell behavior, in order to make predictions on how the mechanisms work in real cells."
Bentley recently published a review article in the April 28 issue of Developmental Cell together with CVBR investigator Erzsebet Ravasz Regan, PhD, and Andrew Philippides, PhD, of the University of Sussex, United Kingdom. Their research examines the growing field of computer simulations in vascular biology focusing on cell biology.
Bentley explains: "The Adaptive Systems field traditionally draws on animal/insect behavior and cognition to come to understand general principles and inspire robotics capable of intelligent, adaptive behavior.
But [with this research]we wanted to highlight that it can also be a very useful in cell biology, in other words, to understand single to collective cell behavior in complex systems, such as in blood vessel growth."
Using a collaborative approach, Bentley and Holger Gerhardt's, PhD, team at the Univerity of London's Cancer Research Institute, made an unexpected discovery. During angiogenesis, the endothelium continuously sprouts cells into various migratory states. These states appear to be regulated by different cell to cell adhesions and protrusions that drive vascular organization. This study was published last month in Nature Cell Biology .
During blood vessel formation, certain molecules tell endothelial cells to take on different characteristics: some become "polarized tip cells"— others become "stalk cells."
Together these two cell types form new capillaries.
Tip and stalk cells were thought to have specialized roles, with tip cells leading and stalk cells following. But this recent research suggests they frequently switch positions.
Stalk cells can overtake tip cells as the leading edge to form a new blood vessel.
Previous studies of endothelial rearrangements suggested the adhesion molecule VE-cadherin plays a key role in helping endothelial cells stick together.
"Our team had linked rearranging behavior of endothelial cells during vessel sprouting to a signaling pathway called Notch," explains Bentley. "But what Notch regulates to generate movement and how it may interplay with VE-cadherin has remained elusive. It's also been unclear how pathological conditions such as cancer may affect the rearrangement process or whether rearrangement defects may contribute to disease."
Bentley and Gerhardt propose that when endothelial cells are stimulated by vascular endothelial growth factor (VEGF) and not inhibited by Notch signaling — they become "active" or "turned on."
Once "active," cells will either form a new branch as tip cells or "shuffle up" through an existing sprout using cell rearrangement mechanisms.
Their new work in Nature Cell Biology validated simulation experiments in the lab, predicting that Notch regulates shuffling movement using VE-cadherin adhesion molecules.
"We identified that feedback regulation between VEGF and Notch signaling results in different levels of adhesion [through VE-cadherin] and junctional cortex movements between cells in the sprout. These movements actually drive cell rearrangement and tip cell competition," says Bentley.
The team also found that in cancer development and progression, there is a loss of interaction between VEGF and Notch over cell movement. This leads to more uniform adhesion between cells with clustered regions of cells appearing, trapped in an all-active or all-inhibited state.
"When we let Simulant cells loose in a simple simulated tumor environment, their collective behavior changed dramatically," says Bentley. "The cells go through cyclic phases of adhesion and junctional movements as a group. They all clamber to move at once or all remain still. In either case they are getting nowhere. The disrupted rearrangement provides a new explanation for the enlarged blood vessels we see in disease pathologies, such as in mouse models of tumor or retinopathy."
This research approach offers useful new principles for studying basic and complex questions about health and disease. "We hope that our work proves that cell level theory can be made accessible and when integrated with experiments, can help unravel the complexities and dynamics of living systems and disease," adds Bentley.
 Do Endothelial Cells Dream of Eclectic Shape?
Endothelial cells (ECs) exhibit dramatic plasticity of form at the single- and collective-cell level during new vessel growth, adult vascular homeostasis, and pathology. Understanding how, when, and why individual ECs coordinate decisions to change shape, in relation to the myriad of dynamic environmental signals, is key to understanding normal and pathological blood vessel behavior. However, this is a complex spatial and temporal problem. In this review we show that the multidisciplinary field of Adaptive Systems offers a refreshing perspective, common biological language, and straightforward toolkit that cell biologists can use to untangle the complexity of dynamic, morphogenetic systems
 The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis
Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies.
Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School, and currently ranks third in National Institutes of Health funding among independent hospitals nationwide.
The BIDMC health care team includes Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, Signature Health Care, Commonwealth Hematology-Oncology, Beth Israel Deaconess HealthCare, Community Care Alliance, and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Senior Life and is a research partner of Dana-Farber/Harvard Cancer Center. BIDMC is the official hospital of the Boston Red Sox. For more information, visithttp://www.bidmc.org.
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