Understanding Endothelial Flow-Migration in Vascular Remodelling

Alapfogalmak

Endothelial cells migrate directionally driven by dual force-fields of shear stress and VEGFA gradients.

Kivonat

The study investigates endothelial cell migration during vascular remodelling, revealing a shift from veins to arteries. A computational model incorporating shear stress and VEGFA cues explains the observed population shifts. Cdc42 mediates EC movement towards arteries, while Rac1 plays a minor role. In vitro experiments show impaired migration with Cdc42 depletion and accelerated migration with Rac1 depletion. Heterogeneous migration patterns suggest a balance between competing forces for effective vascular remodelling.

Statisztikák

"High migration rates require only weak flow-migration coupling, whereas low migration rates require strong coupling to the flow direction."
"Functional analysis identified Cdc42 as the critical mediator of overall population movement from veins to arteries."
"Computational simulation of stochastically labelled ECs randomly seeded in a vein-plexus-artery sector illustrated that the observed population shift cannot be explained by random walk."
"Phase diagram analysis predicted that already a low coupling strength is sufficient to drive ECs towards the artery if the movement rate is sufficiently high."

Idézetek

"The ability to label cells at precise locations depends on selective genetic tools driving expression at discrete time points."
"ECs move against blood flow up the gradient of increasing shear levels."
"Cdc42 is essential for cells to reach the artery, with no evidence for any directional movement against the shear gradient."

Főbb Kivonatok

Reconstructing stochastic cell population trajectories reveals regulators and heterogeneity of endothelial flow-migration coupling driving vascular remodelling

by Giese,W., Ro... : www.biorxiv.org 05-30-2023

https://www.biorxiv.org/content/10.1101/2023.05.30.542799v3

Mélyebb kérdések

How does heterogeneity in EC migration contribute to maintaining balanced vascular networks?

Heterogeneity in endothelial cell (EC) migration plays a crucial role in maintaining balanced vascular networks by ensuring proper vessel formation and remodeling. In the context of the study, the observed heterogeneous movement of ECs allows for a dynamic distribution of cells within the developing vasculature. This diversity in migration patterns prevents overcrowding or rarefaction of vessels, contributing to the overall structural integrity and functionality of the vascular network.
Specifically, this heterogeneity enables some ECs to migrate towards arteries while others move away from them, creating a balanced distribution along the vein-to-artery axis. Without this variability in migration behavior, there would be an imbalance in vessel density and connectivity, leading to potential malformations or inefficiencies in blood flow regulation. By allowing different subsets of ECs to respond differently to chemotactic cues and mechanical forces, heterogeneity ensures that vessels are appropriately populated and interconnected.
Furthermore, by incorporating diverse migratory behaviors among EC populations, such as directional movement against flow or preferential migration towards specific regions like sprouting fronts or arterial connections, heterogeneity contributes to adaptability and resilience within vascular networks. This flexibility allows for efficient responses to changing environmental cues during development and maintenance processes.

What implications do these findings have for understanding vascular malformations?

The findings regarding endothelial cell (EC) migration dynamics have significant implications for understanding vascular malformations. Vascular malformations often arise due to disruptions in normal developmental processes that lead to structural abnormalities or functional deficiencies within blood vessels. Understanding how ECs migrate during development provides insights into how these processes can go awry and contribute to malformations.
One key implication is that alterations in the balance between VEGFA-driven chemotaxis and shear stress-induced directional movement may lead to aberrant vessel patterning and connectivity seen in various types of vascular malformations. For example, if there is a loss of heterogeneity resulting in all ECs migrating uniformly towards certain regions without responding appropriately to local cues or mechanical forces, it could result in misaligned vessels or abnormal branching patterns.
Additionally, dysregulation of signaling pathways involved in mediating EC migration behaviors—such as those controlled by small Rho GTPases like Cdc42—can disrupt coordinated vessel formation processes leading to malformations. The study's focus on Cdc42 depletion impairing flow-migration coupling highlights how molecular mechanisms regulating cell motility are critical for proper vascular development.
Overall, these findings underscore the importance of precise control over EC migration dynamics for establishing healthy vasculature during embryonic development—and provide valuable insights into potential mechanisms underlying pathological conditions associated with vascular malformation disorders.

How can computational models be further refined to incorporate additional factors influencing endothelial cell migration?

To enhance computational models exploring endothelial cell (EC) migration dynamics further—to incorporate additional factors influencing their movements—a few key strategies can be employed:

Integration of Cell-Cell Interactions: Including interactions between neighboring cells through adhesion molecules like VE-cadherin can influence collective migratory behavior observed during angiogenesis.

Incorporation of Extracellular Matrix Dynamics: Modeling how ECM components guide cell movement through physical constraints or biochemical signaling gradients adds another layer of complexity relevant for realistic simulations.

Accounting for Mechanical Forces: Considering biomechanical aspects such as substrate stiffness affecting cytoskeletal organization—or fluid shear stress impacting cellular responses—provides more physiological relevance.

Temporal Dynamics: Incorporating time-dependent changes reflecting developmental stages helps capture evolving migratory patterns over extended periods accurately.

5Multi-Scale Modeling: Combining macroscopic tissue-level modeling with microscopic single-cell simulations offers comprehensive insights into emergent properties arising from individual cellular behaviors interacting at different scales.
By integrating these elements into computational models alongside existing factors like chemoattractant gradients and force fields driving directed motion—the refinement process will yield more sophisticated tools capable not only predicting but also explaining complex spatiotemporal aspects governing endothelial cell migrations essential for forming functional vasculature structures