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Our research at Ludwig Oxford covers three interconnected questions:

1. What makes blood vessels molecularly different from each other?

Heterogeneity in the vasculature, both in physiological systems and in tumours, is readily evident to the naked eye, yet molecular definitions of this heterogeneity are lacking, making the vasculature challenging to study. This work aims to identify the unique transcriptional signatures for endothelial sub-types.

2. How do signalling pathways contribute to vessel growth?

Although the Vascular Endothelial Growth Factor (VEGF) pathway has been the primary focus for efforts to modulate vascular growth, many other signalling cascades are involved in vascular development. However, the roles of different pathways during vessel growth, and interactions between them, have been challenging to establish. This work aims to connect different signalling pathways with a transcriptional response.

3. Which regulatory pathways are crucial during disordered vessel growth?

The continued expression of pro-angiogenic factors in tumours as they grow results in the constant induction of new blood vessels, and concurrently stimulates other vessels to mature. Consequently, the complex mixture of vessels in tumours is unlike anything seen during physiological vascularisation. Conversely, vessel growth in adult tissues after damage or trauma is often aberrant or insufficient, contributing to a failure of adequate tissue regeneration. We use our delineated enhancer range and transcription factor hierarchies to study these processes in novel ways.

 

The main research themes in the De Val group. Figure title: Enhancer analysis has elucidated multiple independent regulatory cascades governing endothelial behavior. Arterial endothelial cells (Sacilotto et al (2013) PNAS) An unknown factor activates SOXF to induce the expression of Notch1 and Dll4, Flk1, Nrp1 to induce arterial endothelial cells. Notch1 also activates Dll4, Flk1, Nrp1. Angiogenic endothelial cells (Sacilotto, Chouliaras (2016) Genes Dev): VEGFA activates EP300 that activates MEF2, and inihibits HDAC that inhibits MEF2. MEF2 induces the expression of Hlx, Ets1 and Elk3. Ets1 operates a positive feedback loop to further activate MEF2. MEF2 also activates the expression of Dll4 (which is also partially activated by Ets1 and Elk3). Hlx, Ets1, Elk3 and Dll4 induce angiogenic endothelial cells. Venous endothelial cells (Neal et al (2019) Nature Commun): BMP4 activates ALK3 which activates SMAD1/5. SMAD1/5 stimulates the transcription of Ephb4, Nrf2f2 and Emcn to induce venous endothelial cells.