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Vascular simulation research reveals new mechanism that switches in disease
Date:5/7/2014

ratory states, regulated by differential cell-cell adhesions and protrusive activities that drive proper vascular organization.

During blood vessel formation, certain molecules and cues tell endothelial cells to take on different characteristics, with some becoming "polarized tip cells" and other becoming "stalk cells." Together these two cell types form new capillaries. Tip and stalk cells were previously thought to have established roles, with tip cells leading the way and stalk cells following along to create a vessel tube, but recent research has suggested that endothelial cells are much more spontaneous and actually undergo dynamic changes and frequently switch positions, with stalk cells overtaking tip cells at the leading edge of a new blood vessel.

Previous studies of endothelial rearrangements suggested the adhesion molecule VE-cadherin plays a key role in helping endothelial cells to 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 are "active" and can either form a new branch as tip cells or "shuffle up" through the existing sprout by cell rearrangement mechanisms. Their new work in Nature Cell Biology validated simulation predictions in vivo, demonstrating that Notch regulates shuffling movement via VE-cadherin adhesion.

"We identified that feedback regulation between VEGF and Notch signaling results in different levels of adhesion [through VE-cadherin] and junctional corte
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Contact: Bonnie Prescott
bprescot@bidmc.harvard.edu
617-667-7306
Beth Israel Deaconess Medical Center
Source:Eurekalert

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