Angiopoietin-like 2 is essential to aortic valve development in mice

Aortic valve (AoV) abnormalities during embryogenesis are a major risk for the development of aortic valve stenosis (AVS) and cardiac events later in life. Here, we identify an unexpected role for Angiopoietin-like 2 (ANGPTL2), a pro-inflammatory protein secreted by senescent cells, in valvulogenesis. At late embryonic stage, mice knocked-down for Angptl2 (Angptl2-KD) exhibit a premature thickening of AoV leaflets associated with a dysregulation of the fine balance between cell apoptosis, senescence and proliferation during AoV remodeling and a decrease in the crucial Notch signalling. These structural and molecular abnormalities lead toward spontaneous AVS with elevated trans-aortic gradient in adult mice of both sexes. Consistently, ANGPTL2 expression is detected in human fetal semilunar valves and associated with pathways involved in cell cycle and senescence. Altogether, these findings suggest that Angptl2 is essential for valvulogenesis, and identify Angptl2-KD mice as an animal model to study spontaneous AVS, a disease with unmet medical need. Mice knockdown for Angiopoietin-like 2 (Angptl2) exhibit spontaneous aortic valve stenosis associated with a decrease in Notch signalling and an imbalance in cell apoptosis, senescence and proliferation during embryonic valve remodelling stage.

Automated summary

A study has found that Angiopoietin-like 2 (ANGPTL2) plays a crucial role in valve development during embryogenesis. Knockout mice for the Angptl2 gene exhibit abnormal thickening of the valve leaflets and dysregulation in the balance between cell apoptosis, senescence, and proliferation, as well as a decrease in Notch signaling. These abnormalities lead to spontaneous aortic valve stenosis in adult mice.