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Dynamic endothelial cell rearrangements drive developmental vessel regression.

Franco CA, Jones ML, Bernabeu MO, Geudens I, Mathivet T, Rosa A, Lopes FM, Lima AP, Ragab A, Collins RT, Phng LK, Coveney PV, Gerhardt H - PLoS Biol. (2015)

Bottom Line: Patterning of functional blood vessel networks is achieved by pruning of superfluous connections.The cellular and molecular principles of vessel regression are poorly understood.Establishing and analyzing the first axial polarity map of all endothelial cells in a remodeling vascular network, we propose that balanced movement of cells maintains the primitive plexus under low shear conditions in a metastable dynamic state.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology Laboratory, London Research Institute-Cancer Research UK, Lincoln's Inn Laboratories, London, United Kingdom; Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.

ABSTRACT
Patterning of functional blood vessel networks is achieved by pruning of superfluous connections. The cellular and molecular principles of vessel regression are poorly understood. Here we show that regression is mediated by dynamic and polarized migration of endothelial cells, representing anastomosis in reverse. Establishing and analyzing the first axial polarity map of all endothelial cells in a remodeling vascular network, we propose that balanced movement of cells maintains the primitive plexus under low shear conditions in a metastable dynamic state. We predict that flow-induced polarized migration of endothelial cells breaks symmetry and leads to stabilization of high flow/shear segments and regression of adjacent low flow/shear segments.

No MeSH data available.


Related in: MedlinePlus

Working model for flow-induced remodeling through directional migration.Schematized prototypic vessel network in a developing retina. Endothelial cell axial polarity is indicated by Golgi position; flow direction (arrows) and velocity (thickness), producing luminal membrane shear stress, are depicted by light blue lines. Vessels in the distal primitive plexus are exposed to low, oscillatory, or no-flow, and vessels closer to developing arteries are exposed to higher blood flow velocities. High blood flow leads to increased levels of shear stress, which induces robust polarization of endothelial cells against flow. Increasing flow asymmetries between juxtaposed vessel segments trigger endothelial migration away from low flow regions (black arrows), inducing vessel segment regression.
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pbio.1002125.g006: Working model for flow-induced remodeling through directional migration.Schematized prototypic vessel network in a developing retina. Endothelial cell axial polarity is indicated by Golgi position; flow direction (arrows) and velocity (thickness), producing luminal membrane shear stress, are depicted by light blue lines. Vessels in the distal primitive plexus are exposed to low, oscillatory, or no-flow, and vessels closer to developing arteries are exposed to higher blood flow velocities. High blood flow leads to increased levels of shear stress, which induces robust polarization of endothelial cells against flow. Increasing flow asymmetries between juxtaposed vessel segments trigger endothelial migration away from low flow regions (black arrows), inducing vessel segment regression.

Mentions: Based on the present observations, we propose that endothelial cells migrate and rearrange dynamically, not only in sprouts, as shown previously [13,17,18], but also in the newly formed and the remodeling plexus. In the primitive plexus, this migratory behavior lacks an overt directionality and is thus balanced, enabling a symmetric distribution of cells throughout all segments, thus forming a uniform primitive plexus. When flow creates sufficient high shear forces on the endothelial luminal surface, this new directional force breaks the symmetry and drives polarization against the blood flow direction. This polarization directs migration of cells in low-flow or oscillatory flow segments towards the high flow segments, thus destabilizing the segment. As a consequence, there will be a net movement of cells out of the low-flow branch into the higher flow branch, thus leading to regression of the former and stabilization of the latter. Similarly, live-imaging in zebrafish brain vasculature demonstrated that regressing vessel segments exhibit low flow, which decreased irreversibly prior to the onset of regression [6]. Interestingly, the set value for shear stress when vessels enter the regression program is variable, but seems to depend on shear stress levels on juxtaposed vessel segments [6]. Taken together, we propose that increasing flow asymmetry between juxtaposed vessel segments is the trigger for developmental vessel regression (Fig 6). At the regressing segment, low-flow conditions are insufficient to establish strong continuous cell polarity within the segment. Where these cells connect to and sense higher flow in neighboring segments, the resulting polarity will lead to “attraction” of cells into the high-flow segment. In principle, axial polarity can be a component of directional cell migration or a consequence of the shear forces exerted onto the cell. Thus the migratory polarization and flow-induced polarization may be distinct events. Recent work by the Siekmann team, however, identified movement of endothelial cells in a remodeling plexus from the vein to the artery [19], thus against the predicted direction of flow. Therefore, it is also possible that the migration and flow-induced polarity events are tightly linked. The observed vessel stenosis could also be a trigger of poor perfusion, and thus polarity, or the consequence of the migratory behavior and attraction of the cells out of this segment and into the neighboring one.


Dynamic endothelial cell rearrangements drive developmental vessel regression.

Franco CA, Jones ML, Bernabeu MO, Geudens I, Mathivet T, Rosa A, Lopes FM, Lima AP, Ragab A, Collins RT, Phng LK, Coveney PV, Gerhardt H - PLoS Biol. (2015)

Working model for flow-induced remodeling through directional migration.Schematized prototypic vessel network in a developing retina. Endothelial cell axial polarity is indicated by Golgi position; flow direction (arrows) and velocity (thickness), producing luminal membrane shear stress, are depicted by light blue lines. Vessels in the distal primitive plexus are exposed to low, oscillatory, or no-flow, and vessels closer to developing arteries are exposed to higher blood flow velocities. High blood flow leads to increased levels of shear stress, which induces robust polarization of endothelial cells against flow. Increasing flow asymmetries between juxtaposed vessel segments trigger endothelial migration away from low flow regions (black arrows), inducing vessel segment regression.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401640&req=5

pbio.1002125.g006: Working model for flow-induced remodeling through directional migration.Schematized prototypic vessel network in a developing retina. Endothelial cell axial polarity is indicated by Golgi position; flow direction (arrows) and velocity (thickness), producing luminal membrane shear stress, are depicted by light blue lines. Vessels in the distal primitive plexus are exposed to low, oscillatory, or no-flow, and vessels closer to developing arteries are exposed to higher blood flow velocities. High blood flow leads to increased levels of shear stress, which induces robust polarization of endothelial cells against flow. Increasing flow asymmetries between juxtaposed vessel segments trigger endothelial migration away from low flow regions (black arrows), inducing vessel segment regression.
Mentions: Based on the present observations, we propose that endothelial cells migrate and rearrange dynamically, not only in sprouts, as shown previously [13,17,18], but also in the newly formed and the remodeling plexus. In the primitive plexus, this migratory behavior lacks an overt directionality and is thus balanced, enabling a symmetric distribution of cells throughout all segments, thus forming a uniform primitive plexus. When flow creates sufficient high shear forces on the endothelial luminal surface, this new directional force breaks the symmetry and drives polarization against the blood flow direction. This polarization directs migration of cells in low-flow or oscillatory flow segments towards the high flow segments, thus destabilizing the segment. As a consequence, there will be a net movement of cells out of the low-flow branch into the higher flow branch, thus leading to regression of the former and stabilization of the latter. Similarly, live-imaging in zebrafish brain vasculature demonstrated that regressing vessel segments exhibit low flow, which decreased irreversibly prior to the onset of regression [6]. Interestingly, the set value for shear stress when vessels enter the regression program is variable, but seems to depend on shear stress levels on juxtaposed vessel segments [6]. Taken together, we propose that increasing flow asymmetry between juxtaposed vessel segments is the trigger for developmental vessel regression (Fig 6). At the regressing segment, low-flow conditions are insufficient to establish strong continuous cell polarity within the segment. Where these cells connect to and sense higher flow in neighboring segments, the resulting polarity will lead to “attraction” of cells into the high-flow segment. In principle, axial polarity can be a component of directional cell migration or a consequence of the shear forces exerted onto the cell. Thus the migratory polarization and flow-induced polarization may be distinct events. Recent work by the Siekmann team, however, identified movement of endothelial cells in a remodeling plexus from the vein to the artery [19], thus against the predicted direction of flow. Therefore, it is also possible that the migration and flow-induced polarity events are tightly linked. The observed vessel stenosis could also be a trigger of poor perfusion, and thus polarity, or the consequence of the migratory behavior and attraction of the cells out of this segment and into the neighboring one.

Bottom Line: Patterning of functional blood vessel networks is achieved by pruning of superfluous connections.The cellular and molecular principles of vessel regression are poorly understood.Establishing and analyzing the first axial polarity map of all endothelial cells in a remodeling vascular network, we propose that balanced movement of cells maintains the primitive plexus under low shear conditions in a metastable dynamic state.

View Article: PubMed Central - PubMed

Affiliation: Vascular Biology Laboratory, London Research Institute-Cancer Research UK, Lincoln's Inn Laboratories, London, United Kingdom; Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisboa, Portugal.

ABSTRACT
Patterning of functional blood vessel networks is achieved by pruning of superfluous connections. The cellular and molecular principles of vessel regression are poorly understood. Here we show that regression is mediated by dynamic and polarized migration of endothelial cells, representing anastomosis in reverse. Establishing and analyzing the first axial polarity map of all endothelial cells in a remodeling vascular network, we propose that balanced movement of cells maintains the primitive plexus under low shear conditions in a metastable dynamic state. We predict that flow-induced polarized migration of endothelial cells breaks symmetry and leads to stabilization of high flow/shear segments and regression of adjacent low flow/shear segments.

No MeSH data available.


Related in: MedlinePlus