NOTCH1 regulates matrix gla protein and calcification gene networks in human valve endothelium

Area of Science:

• Cardiovascular Biology
• Endothelial Cell Biology
• Molecular Medicine

Background:

• Valvular and vascular calcification contribute significantly to cardiovascular disease.
• NOTCH1 signaling is crucial for vascular and valvular endothelium, with mutations linked to calcific aortic valve disease.
• Shear stress is hypothesized to inhibit calcification, but its molecular mechanisms in the aortic valve are not fully understood.

Purpose of the Study:

• To investigate the genome-wide effects of shear stress and NOTCH1 signaling on human aortic valve endothelial cells (HAVECs).
• To elucidate the molecular pathways by which NOTCH1 and shear stress influence genes involved in calcification.

Main Methods:

• Primary human aortic valve endothelial cells (HAVECs) underwent mRNA sequencing.
• NOTCH1 was manipulated (knockdown) in the presence or absence of shear stress.
• Gene expression changes, including those related to atherosclerosis and endochondral ossification, were analyzed.

Main Results:

• NOTCH1 regulates the expression of connexin 40 (GJA5) and repressors of endochondral ossification.
• Matrix Gla Protein (MGP), an inhibitor of soft tissue calcification, was found to be regulated by NOTCH1.
• Shear stress activated NOTCH1 signaling and MGP expression in a NOTCH1-dependent manner.
• NOTCH1 directly regulated endothelial MGP expression in vivo.

Conclusions:

• Shear stress activates NOTCH1 in HAVECs, which in turn downregulates osteoblast-like gene networks implicated in tissue calcification.
• These findings highlight a novel mechanism involving shear stress, NOTCH1, and MGP in the regulation of valvular calcification.
• Targeting the shear stress-NOTCH1-MGP axis may offer therapeutic strategies for preventing cardiovascular calcification.