Atheroprotective laminar flow inhibits Hippo pathway effector YAP in endothelial cells

Abstract

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.

Micropatterning as a tool to identify regulatory triggers and kinetics of actin-mediated endothelial mechanosensing

“…The regulation of YAP under shear stress has recently been controversially discussed in terms of an activating (Nakajima et al, 2017) or inactivating (Xu et al, 2016) response to this stimulus. Therefore, it is possible that YAP is only activated in response to distinct mechanical stimuli, as it has been suggested for disturbed flow conditions .…”

The role of Hippo/yes‐associated protein signalling in vascular remodelling associated with cardiovascular disease

“…As a result, reduced YAP activity inhibited c‐Jun N‐terminal kinase signalling and down‐regulated the expression of inflammatory factors such as cyclin A1 and CCL2 in a TEAD‐independent manner (Wang et al, ). In contrast, laminar flow decreased YAP nuclear localization and activity in human ECs (Xu et al, ; Wang et al, ), which indicated an atheroprone effect of YAP in response to different blood flow (Figure ). These data, coupled with findings that the suppression of disturbed flow‐induced monocyte attachment to ECs by statin was attenuated by YAP/TAZ inhibition (Wang et al, ), provide a rationale for considering YAP a potent therapeutic target in atherosclerosis.…”

YAP and the RhoC regulator ARHGAP18, are required to mediate flow-dependent endothelial cell alignment

“…The Yes-associated protein (YAP), a transcriptional coactivator of the HIPPO family, is a mechanotransduction protein that controls proliferation, cell shape and organ size [13][14][15]. Recently YAP has also been linked to the response of ECs to laminar flow [16] and YAP activation can promote expression of an inflammatory gene profile [17]. The regulation of the activity of YAP is complex.…”