TY - JOUR
T1 - Endothelial cells signaling and patterning under hypoxia
T2 - a mechanistic integrative computational model including the Notch-Dll4 pathway
AU - Oliveira, Rebeca Hannah de Melo
AU - Annex, Brian H.
AU - Popel, Aleksander S.
N1 - Publisher Copyright:
Copyright © 2024 Oliveira, Annex and Popel.
PY - 2024
Y1 - 2024
N2 - Introduction: Several signaling pathways are activated during hypoxia to promote angiogenesis, leading to endothelial cell patterning, interaction, and downstream signaling. Understanding the mechanistic signaling differences between endothelial cells under normoxia and hypoxia and their response to different stimuli can guide therapies to modulate angiogenesis. We present a novel mechanistic model of interacting endothelial cells, including the main pathways involved in angiogenesis. Methods: We calibrate and fit the model parameters based on well-established modeling techniques that include structural and practical parameter identifiability, uncertainty quantification, and global sensitivity. Results: Our results indicate that the main pathways involved in patterning tip and stalk endothelial cells under hypoxia differ, and the time under hypoxia interferes with how different stimuli affect patterning. Additionally, our simulations indicate that Notch signaling might regulate vascular permeability and establish different Nitric Oxide release patterns for tip/stalk cells. Following simulations with various stimuli, our model suggests that factors such as time under hypoxia and oxygen availability must be considered for EC pattern control. Discussion: This project provides insights into the signaling and patterning of endothelial cells under various oxygen levels and stimulation by VEGFA and is our first integrative approach toward achieving EC control as a method for improving angiogenesis. Overall, our model provides a computational framework that can be built on to test angiogenesis-related therapies by modulation of different pathways, such as the Notch pathway.
AB - Introduction: Several signaling pathways are activated during hypoxia to promote angiogenesis, leading to endothelial cell patterning, interaction, and downstream signaling. Understanding the mechanistic signaling differences between endothelial cells under normoxia and hypoxia and their response to different stimuli can guide therapies to modulate angiogenesis. We present a novel mechanistic model of interacting endothelial cells, including the main pathways involved in angiogenesis. Methods: We calibrate and fit the model parameters based on well-established modeling techniques that include structural and practical parameter identifiability, uncertainty quantification, and global sensitivity. Results: Our results indicate that the main pathways involved in patterning tip and stalk endothelial cells under hypoxia differ, and the time under hypoxia interferes with how different stimuli affect patterning. Additionally, our simulations indicate that Notch signaling might regulate vascular permeability and establish different Nitric Oxide release patterns for tip/stalk cells. Following simulations with various stimuli, our model suggests that factors such as time under hypoxia and oxygen availability must be considered for EC pattern control. Discussion: This project provides insights into the signaling and patterning of endothelial cells under various oxygen levels and stimulation by VEGFA and is our first integrative approach toward achieving EC control as a method for improving angiogenesis. Overall, our model provides a computational framework that can be built on to test angiogenesis-related therapies by modulation of different pathways, such as the Notch pathway.
KW - angiogenesis
KW - endothelial cells
KW - hypoxia
KW - mathematical modeling
KW - systems biology
UR - http://www.scopus.com/inward/record.url?scp=85186877854&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85186877854&partnerID=8YFLogxK
U2 - 10.3389/fphys.2024.1351753
DO - 10.3389/fphys.2024.1351753
M3 - Article
AN - SCOPUS:85186877854
SN - 1664-042X
VL - 15
JO - Frontiers in Physiology
JF - Frontiers in Physiology
M1 - 1351753
ER -