ECSiTe · Endothelial Cell Signature in the Total Environment
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2021-07-01 → 2023-08-22
- EU contribution
- €166,320
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Endothelial Cell Signature in the Total Environment
Endothelial cells (ECs) line the inner part of blood vessels and are constantly exposed to mechanical forces. Flow shear stress levels change across the vasculature ranging from 5 to 20-70 dynes/cm2 in veins and aortic valves, respectively. The sensation of shear stress by ECs depends on the tissue stiffnesses, being 0.5-4 kPa in brain, or more than 100 kPa in the aortic valves. Though ECs sense both mechanical cues simultaneously, they have been classically studied separately. Their combined effects, however, could be behind the EC heterogeneity, crucial for the proper function of some organs, but probably also responsible for the low efficiency of vascular-related treatments. Understanding how shear stress and stiffness modulate the ECs behavior would provide new tools towards more specialized tissue engineering and vascular repair approaches. The ECSiTe project addresses this by studying the interplay of fluid shear stress and tissue stiffness in the modulation of the EC gene expression (aim1, working package 1, WP1). Then, the effect of organ-specific basement membrane proteins in organ-specific ECs is studied (aim2, WP2). Finally, the acquired knowledge is integrated to differentiate the contribution of the microenvironment to the ECs heterogeneity (aim3, WP3). Across 14 combinations of shear stress and stiffness, genes being modulated by shear stress or stiffness alone were identified. Importantly, interaction effects between both mechanical cues were identified in 603 genes, related to important cardiovascular processes, such as the migration of ECs. These results correlated with morphological changes in the ECs, with implications in the transcriptional activity of YAP1, an important mechanotransducer. Now, the contribution of organ-specific basement membrane proteins on the modulation of the EC heterogeneity is being addressed. This data is the first to investigate in a large-scale and non-biased approach the role of the interaction of shear stress and tissue stiffness in the vasculature.
Data: CORDIS, © European Union
Project objective
Endothelial cells (ECs) specialize towards tissue-specific needs by shaping their phenotypes in response to microenvironmental stimuli, becoming a highly heterogeneous population. Overlooking the EC heterogenic nature most likely underlies the low efficacy and side-effects of broad-spectrum treatments for vascular bed-specific diseases. However, little is known on the interplay between the factors regulating the EC signatures, and tissue engineering research has essentially used standard and poorly differentiated ECs. The objective of this proposal is to investigate the mechanisms by which tissue-specific mechanical, biochemical and genetic factors interact to regulate EC signatures. To do so, brain and aortic valve ECs –non-standard and highly specialized EC types– will be used. First, by using custom-made hydrogels and a flow chamber device, a combination of different levels of tissue stiffness and shear stress will be applied to ECs in culture. The impact and interaction of both mechanical forces on EC features will be determined by analysing changes in EC phenotypes and in gene expression profiles. Then, brain and valve-specific mechanical forces will be selected, and brain and valve ECs will be cultured under organ-matching mechanical forces but under organ-switched biochemical factors. Because these ECs have strong signatures, by analysing phenotypical shifts, the impact of tissue-specific biochemical factors on EC signatures will be determined. Finally, the genetic impact on brain and valve EC phenotypes and the capability of modulating these through microenvironmental design will be studied by analysing phenotypical shifts after culturing brain and valve ECs under organ-switched total (mechanical and biochemical) environments. In a nutshell, this proposal will provide new knowledge in how specialized ECs integrate the different factors regulating their heterogeneity, leading to new future perspectives on tissue-specific vascular bed repair strategies.
Original text from CORDIS.
Participants
- KATHOLIEKE UNIVERSITEIT LEUVEN · LeuvenCoordinatorBelgium
Links
- View on CORDIS
- DOI: 10.3030/101025264
- https://gbiomed.kuleuven.be/english/research/50000635/jones-lab-group
Data: CORDIS, © European Union