Moreover, systemic deletion of Bmal1 also caused endothelial dysfunction and vascular stiffness due to attenuated Akt and nitric oxide signaling [43], increased expression of the homeostasis-related glycoprotein Von Willebrand factor (vWF) [44], increased production of reactive oxygen species (ROS) by superoxides and uncoupling of nitric oxide synthase [45,46], and dysfunction of matrix metalloproteinase (MMP) 2 and 9 [47]. This evidence concerns the gene VWF and endothelial dysfunction.