Local fluid shear stress operates a molecular switch to drive fetal semilunar valve extension

Background While much is known about the genetic regulation of early valvular morphogenesis, mechanisms governing fetal valvular growth and remodeling remain unclear. Hemodynamic forces strongly influence morphogenesis, but it is unknown whether or how they interact with valvulogenic signaling programs. Side‐specific activity of valvulogenic programs motivates the hypothesis that shear stress pattern‐specific endocardial signaling controls the elongation of leaflets. Results We determined that extension of the semilunar valve occurs via fibrosa sided endocardial proliferation. Low OSS was necessary and sufficient to induce canonical Wnt/β‐catenin activation in fetal valve endothelium, which in turn drives BMP receptor/ligand expression, and pSmad1/5 activity essential for endocardial proliferation. In contrast, ventricularis endocardial cells expressed active Notch1 but minimal pSmad1/5. Endocardial monolayers exposed to LSS attenuate Wnt signaling in a Notch1 dependent manner. Conclusions Low OSS is transduced by endocardial cells into canonical Wnt signaling programs that regulate BMP signaling and endocardial proliferation. In contrast, high LSS induces Notch signaling in endocardial cells, inhibiting Wnt signaling and thereby restricting growth on the ventricular surface. Our results identify a novel mechanically regulated molecular switch, whereby fluid shear stress drives the growth of valve endothelium, orchestrating the extension of the valve in the direction of blood flow. Key Findings Discovered how arterial cushions extend into leaflets Identify local endocardial mechanosensitive switch to drive local tissue growth. These results inform mechanobiological mechanisms of congenital valve malformation.