Unraveling the role of transcription factor Prdm16 in regulating the cellular and (epi)genetic landscape of atherosclerosis at single-cell resolution

Our cardiovascular system is the first organ to develop. Diseases affecting it remain the leading cause of death worldwide. A prime factor to consider when designing treatments is that our vascular tree has an arterial and a venous arm, each coated on the inside by a monolayer of endothelial cells with distinct characteristics. An important consequence of this endothelial cell heterogeneity is that diseases are most often restricted to a particular vascular bed. Peripheral arterial disease specifically affects our arteries and is caused by an upstream atherosclerotic obstruction of a feeding artery triggering downstream redirection of blood flow through collateral arteries as a way to resolve impaired oxygen delivery. For an integral understanding of peripheral arterial disease, knowledge is required about both the upstream and downstream arterial events. While previous findings of the host lab have revealed that deficiency for a novel arterial transcription factor compromises arterial flow recovery, it is unknown whether deficiency for this transcription factor also affects the upstream atherosclerosis process. Here, we will use single-cell RNA sequencing, (electron) microscopy and histology to (i) unravel the mechanisms behind the upstream and downstream events occurring during peripheral arterial disease in mice; (ii) investigate by using transgenic mice how these mechanisms are perturbed by (endothelial) deficiency for this novel transcription factor; (iii) where possible, validate our findings in human arterial tissue. Altogether, we expect this integrated approach will offer clues to develop more effective peripheral arterial disease treatments.