Unraveling the cellular landscape and (epi)genetic mechanisms at single-cell resolution and the effect of Prdm16 deficiency during the pathogenesis of pulmonary arterial hypertension

Our vascular system has two loops, the systemic circulation for distribution of oxygen-rich blood to all organs and a pulmonary circulation for re-oxygenation of blood coming from these organs. Both loops have fundamentally different characteristics and it remains undetermined whether the endothelial cells lining the inside of the pulmonary circulation have a unique reaction to diseases. Pulmonary arterial hypertension (PAH) specifically affects the pulmonary arterial circulation whereby an increase in vascular resistance leads to remodeling and dysfunction of the right heart ventricle and eventually death if left untreated. While genetic defects – mostly mutations in bone morphogenetic (BMP) pathway genes – play a role in the pathogenesis of PAH, additional genes and epigenetic factors have also been implicated. While our previous findings have revealed that deficiency for the arterial transcription factor Prdm16 compromises arterial flow recovery in the systemic circulation, it is unknown whether and how Prdm16 deficiency affects the pathogenesis of PAH. Here, we will use a multi-omics approach at single-cell resolution to (i) unravel the (epi)genetic mechanisms behind PAH in mice; (ii) investigate how these mechanisms are perturbed by (endothelial) Prdm16 deficiency; (iii) where possible, validate our findings in newly developed transgenic rats and human tissue. Altogether, we expect this integrated approach will offer clues to develop more effective PAH treatments.