Unravelling the cellular landscape and the up- and downstream molecular mechanisms of peripheral arterial disease at single-cell resolution

Our cardiovascular system is the first organ to develop and diseases affecting it remain the leading death cause 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 (ECs) with distinct characteristics. An important consequence of this EC heterogeneity is that diseases are most often restricted to a particular vascular bed. Peripheral arterial disease (PAD) 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. Hence, for an integral understanding of PAD, knowledge is required about both the upstream and downstream arterial events. While our previous findings have revealed that deficiency for the arterial transcription factor Prdm16 compromises arterial flow recovery, it is unknown whether Prdm16 deficiency also affects the upstream atherosclerosis process. Here, we will use single-cell RNA sequencing to (i) unravel the mechanisms behind the upstream and downstream events occurring during PAD in mice; (ii) investigate how these mechanisms are perturbed by (endothelial) Prdm16 deficiency; (iii) where possible, validate our findings in human arterial tissue. Altogether, we expect this integrated approach will offer clues to develop more effective PAD treatments.