Atheroprotective laminar flow inhibits Hippo pathway effector YAP in endothelial cells

摘要

Atherosclerosis is a mechanobiology-related disease that preferentially develops in the aortic arch (AA) and arterial branches which are exposed to disturbed/turbulent blood flow (DF), but less in thoracic aorta (TA) where the flow pattern is steady laminar flow (LF). Increasing evidence supports that steady laminar flow with high shear stress is protective against atherosclerosis. However, the molecular mechanisms of LF mediated atheroprotection remain incompletely understood. Hippo/YAP (Yes-associated protein) pathway senses and effects mechanical cues, and has been reported to be a master regulator of cell proliferation, differentiation, and tissue homeostasis. Here we show that LF regulates YAP activity in endothelial cells (ECs). We observed that YAP is highly expressed in mouse EC-enriched tissues (lung and aorta) and in human ECs. Furthermore, we found in ApoE^−/−mice and human ECs, LF decreased the levels of nuclear YAP proteins and YAP target gene expression (CTGF and Cyr61) through promoting Hippo kinases LATS1/2-dependent YAP (Ser127) phosphorylation. Functionally, we revealed that YAP depletion in ECs phenocopying LF responses, reduced the expression of cell cycle gene cyclin A1 (CCNA1) and pro-inflammatory gene CCL2 (MCP-1). Taken together, we demonstrate that atheroprotective LF inhibits endothelial YAP activation, which may contributes to LF-mediated ECs quiescence and anti-inflammation.