Endothelial Cell Signature in the Total Environment

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.