Cross Talk between NOTCH Signaling and Biomechanics in Human Aortic Valve Disease Pathogenesis

Abstract

Aortic valve disease is a burgeoning public health problem associated with significant mortality. Loss of function mutations in NOTCH1 cause bicuspid aortic valve (BAV) and calcific aortic valve disease. Because calcific nodules manifest on the fibrosa side of the cusp in low fluidic oscillatory shear stress (OSS), elucidating pathogenesis requires approaches that consider both molecular and mechanical factors. Therefore, we examined the relationship between NOTCH loss of function (LOF) and biomechanical indices in healthy and diseased human aortic valve interstitial cells (AVICs). An orbital shaker system was used to apply cyclic OSS, which mimics the cardiac cycle and hemodynamics experienced by AVICs in vivo. NOTCH LOF blocked OSS-induced cell alignment in human umbilical vein endothelial cells (HUVECs), whereas AVICs did not align when subjected to OSS under any conditions. In healthy AVICs, OSS resulted in decreased elastin (ELN) and α-SMA (ACTA2). NOTCH LOF was associated with similar changes, but in diseased AVICs, NOTCH LOF combined with OSS was associated with increased α-SMA expression. Interestingly, AVICs showed relatively higher expression of NOTCH2 compared to NOTCH1. Biomechanical interactions between endothelial and interstitial cells involve complex NOTCH signaling that contributes to matrix homeostasis in health and disorganization in disease.

Uncoupling the Vicious Cycle of Mechanical Stress and Inflammation in Calcific Aortic Valve Disease

“…The effect of Notch1 inhibition is modulated by mechanical stress, and aortic VICs isolated from Notch1 +/– genotype mice and exposed to mechanical strain exhibit exaggerated αSMA expression, myofibroblastic differentiation and dystrophic calcific nodule formation compared to wild-type VICs ( 163 ). Similarly, exposure of human aortic VICs to oscillatory shear stress (OSS) in combination with a Notch1 inhibitor resulted in increased αSMA expression, where Notch1 inhibition alone resulted in calcific nodule formation with reduced αSMA expression ( 164 ). Genetic variations in NOTCH1 may predispose some individuals to aortic valvular inflammation in response to normal oscillatory shear stress ( 73 ).…”

Prevalence of Bicuspid Aortic Valve in Turner Syndrome Patients Receiving Cardiac MRI and CT: A Meta-Analysis

“…During embryonic development, the aortic root and the aortic valve originate from the second heart field cells. The NOTCH1 gene has been shown to be substantially involved in TAV development [30]. Mutations in the NOTCH1 gene are associated with the presence of BAV and the occurrence of aortic wall deformations [31].…”

Mechanically activated piezo channels modulate outflow tract valve development through the Yap1 and Klf2-Notch signaling axis

“…In zebrafish, the mechanosensitive channels Trpv4 and Trpp2 modulate endocardial calcium signaling and klf2a expression is necessary for valve morphogenesis and downstream pathway activation (Heckel et al, 2015; Steed et al, 2016b). Notch signaling is tightly involved in cellular mechanosensitive responses in human aortic valves (Godby et al, 2014) and Notch1 is a potent mechanosensor in adult arteries (Mack et al, 2017). More recently, it has been shown that stretch-sensitive channels from the Piezo family (Murthy et al, 2017) are important for vascular development (Li et al, 2014; Ranade et al, 2014) and lymphatic valve formation (Nonomura et al, 2018).…”