Mechanoregulation of Valvular Morphogenesis*

Defective heart valve morphogenesis is a major cause of preterm fetal death and premature postnatal tissue failure. While much has been learned over the past 30 years regarding the genetic and molecular agents engaged in valve morphogenesis, much less is known about how these networks contribute to cellular and tissue level responses essential for sculpting initially amorphous globular cushions into elongated, thin, and striated leaflets that are competent for long term biomechanical function. Recent studies from our group and others have highlighted that the local mechanical environment within the fetal heart are essential mediators of proper, and when perturbed defective, valvular growth and maturation. We here clarify the embryonic and fetal mechanical environment and elaborate how these mechanical signals coordinate and integrate both canonical valvulogenic signaling programs and previously understudied cellular migration and traction generating programs towards maturation. As this field deepens in its understanding, new opportunities to engineer molecular therapies to harness mechanotransduction and/or mechanosensation could help rebalance disturbed valvulogenic programming, improve anatomical outcomes at birth, and ultimately extend valve performance.