Single cell investigation of intussusceptive angiogenesis in health and disease.

Perturbed vessel formation contributes to more than 70 diseases. Sprouting Angiogenesis (SA) and Intussusceptive Angiogenesis (IA, or vessel splitting) are the major mechanisms of vessel formation. Of note, IA, a faster way to grow blood vessels compared to SA, is the primary mechanism in the pathophysiological repair of COVID-19 lungs. While SA has been studied in detail, genes that instruct endothelial cells (ECs; cells lining blood vessels) to engage in IA are largely unknown. Compelling studies (including from the host lab) have shown that SA is regulated by specific metabolic pathways. Targeting these pathways blocks SA in pre-clinical mouse models. Based on these findings, I hypothesize that ECs engaging in vessel splitting are characterized and driven by a distinct (metabolic) transcriptome. I will study IA in established and new (COVID-19 lungs) models of vessel splitting using state-of-the-art single cell transcriptomics. I will characterize the transcriptomic signature of ECs at single cell level; identify conserved (metabolic) markers of IA and modulate selected, promising targets in vivo with pharmacological and genetic tools. This proposal capitalizes on the expertise from the host lab and my background in regenerative biology. It is uniquely positioned to provide novel insights in the mechanisms of IA which will foster the development of new blood vessel-centric therapies in malignant disease and for regenerative purposes.