Fig. 7. Summarized evidence for a role of ANGPTL2 as a potentially new essential player in valvulogenesis in mice and human.

At E14.5 during semilunar valve remodelling in mice, the KD of Angptl2 induces a decrease in Notch1 signalling via Integrin α5β1 receptors in AoV leaflets, which in turn deregulates the fine balance between cell apoptosis, senescence and proliferation. Lower apoptosis and senescence combined with higher cellular proliferation induce inadequate AoV maturation, and lead to thickened AoV leaflets at E18. The thickened AoV leaflets during embryogenesis are associated with the development of AVS in adult mice. ANGPTL2 is also enriched in human fetal semilunar valves compared to adult AoV and is associated with pathways related to cell cycle and senescence. Parts of the figure were drawn by using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/). The upper panel was adapted from Lin et al.⁸⁷.