Mechanosensitive Mechanism of Lung Regeneration through Endothelial YAP1

Abstract

Angiogenesis, the formation of new blood capillaries, plays a key role in organ development, homeostasis and regeneration. In addition to chemical factors, mechanical forces control angiogenesis and organ regeneration. We have reported that the mechanosensitive transcriptional co‐activator Yes‐associated protein (YAP1) in endothelial cells (ECs) is necessary for post‐pneumonectomy (PNX) lung growth. Right pulmonary artery (PA) pressure and shear stress increase after left unilateral PNX. However, it remains unknown whether changes in PA pressure and shear stress after PNX control post‐PNX regenerative lung growth through endothelial YAP1 signaling. Here we found that ligation of the right cardiac lobe PA after left PNX further increases right PA pressure and shear stress, upregulates expression of YAP1 and angiogenic factor Tie2, and stimulates post‐PNX lung growth in the remaining non‐occluded lobes. These effects are attenuated in VE‐cadherin‐specific Yap1 knockout mice. Hydrostatic pressure or shear stress applied to cultured human pulmonary arterial ECs also increases the expression and activity of YAP1 and induces EC proliferation and migration in vitro. These results suggest that increases in the right PA pressure together with elevation in shear stress after left PNX stimulate angiogenesis and post‐PNX lung growth through endothelial YAP1. Modulation of the mechanical environment or endothelial YAP1 expression/activity could be an efficient strategy for regenerative lung growth.Support or Funding InformationNIH RO1HL142578