Regulatory pathways controlling venous identity

The circulatory system of mammals is dependent on the formation of two distinct types of blood vessel, arteries and veins. The differences between these two blood vessel types arise due to alternative molecular signals early on in development. However, very little is known about these signals and how vein-specific genes are switched on in veins and off in arteries. Understanding this process is crucial for understanding and treating cardiovascular disease. For example, veins are often used to replace damaged arteries in coronary bypass surgery but often do not correctly adapt, and defective arterial-venous differentiation can lead to enlarged blood vessels at risk of catastrophic ruptures.

This study will look at regions of DNA called enhancers. These enhancer regions control whether a gene is on or off through the binding of proteins called transcription factors. We have found two enhancers which can switch genes on specifically in veins. This project aims to find what transcription factors bind to, and control, these vein-specific enhancers, and to understand what external signals cause this to happen. We will also use these gene switches to make an animal model capable of deleting any gene of interest specifically from veins.

This project will use the identification, analysis and characterisation of two novel venous-specific gene enhancers and their cognate binding transcription factors to understand the transcriptional and signalling pathways that regulate venous identity. While research clearly demonstrates that venous identity in endothelial cells is actively acquired, very little is known about the pathways that control this process. Ephb4 and COUP-TFII play essential roles in the specification and differentiation of veins, yet the manner in which their expression is regulated in venous endothelial cells is not known. In fact, it is still unclear whether their transcription is actively stimulated in veins, or repressed in arteries. Interpreting the results of signalling experiments is still challenging, due to a lack of even basic knowledge of venous gene regulation. The project proposed here will expand our knowledge of venous gene regulation by identifying and analysing enhancers driving Ephb4 and Coup-TFII expression in venous endothelial cells, delineate the key cis-motifs and trans-factors that regulate these enhancers in an unbiased manner, and discern the vascular signalling pathways upstream of this regulation.

Virtually nothing is known about how venous endothelial cells become specified and differentiation. Consequently, this research is anticipated to have a major influence in the vascular developmental biology field and far beyond. This work will be of interest to a wide range of academics, described in detail in the Academic Beneficiary section. In addition, this research will provide key insights into how venous identity is both acquired and maintained, which is anticipated to open new avenues of research into mechanisms that may alter blood vessel identity for therapeutical benefits. For example, this work will be of interest to teams looking to manipulate cells to take on an endothelial, venous or arterial fate with the aim of assisting in repair after ischemic damage.
In addition, although the proposed project is in basic research, understanding how blood vessels take on, and potential can loose, venous identify has potential interest to health care professionals. For example, veins are often used to repair damaged arteries in the heart, and this research may illuminate mechanisms beneficial or detrimental to the survival, and adaptability, of these grafts. The identification of key factors directing venous fate may also provide novel biomarkers to assess the differentiation status of vessels after vascular disease or surgery, and to identify cases of venous graft failure.