KIf2 is an essential regulator of vascular hemodynamic forces in vivo

Hemodynamic responses that control blood pressure and the distribution of blood flow to different organs are essential for survival. Shear forces generated by blood flow regulate hemodynamic responses, but the molecular and genetic basis for such regulation is not known. The transcription factor KLF2 is activated by fluid shear stress in cultured enclothelial cells, where it regulates a large number of vasoactive endothelial genes. Here, we show that KIf2 expression during development mirrors the rise of fluid shear forces, and that enclothelial loss of KIf2 results in lethal embryonic heart failure due to a high-cardiac-output state. KIf2 deficiency does not result in anemia or structural vascular defects, and it can be rescued by administration of phenylephrine, a catecholamine that raises vessel tone. These findings identify KIf2 as an essential hemodynamic regulator in vivo and suggest that hemodynamic regulation in response to fluid shear stress is required for cardiovascular development and function.