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PAR-3 controls endothelial planar polarity and vascular inflammation under laminar flow.

ABSTRACT: Impaired cell polarity is a hallmark of diseased tissue. In the cardiovascular system, laminar blood flow induces endothelial planar cell polarity, represented by elongated cell shape and asymmetric distribution of intracellular organelles along the axis of blood flow. Disrupted endothelial planar polarity is considered to be pro-inflammatory, suggesting that the establishment of endothelial polarity elicits an anti-inflammatory response. However, a causative relationship between polarity and inflammatory responses has not been firmly established. Here, we find that a cell polarity protein, PAR-3, is an essential gatekeeper of GSK3? activity in response to laminar blood flow. We show that flow-induced spatial distribution of PAR-3/aPKC? and aPKC?/GSK3? complexes controls local GSK3? activity and thereby regulates endothelial planar polarity. The spatial information for GSK3? activation is essential for flow-dependent polarity to the flow axis, but is not necessary for flow-induced anti-inflammatory response. Our results shed light on a novel relationship between endothelial polarity and vascular homeostasis highlighting avenues for novel therapeutic strategies.

SUBMITTER: Hikita T

PROVIDER: S-EPMC6123654 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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PAR-3 controls endothelial planar polarity and vascular inflammation under laminar flow.

Hikita Takao T Mirzapourshafiyi Fatemeh F Barbacena Pedro P Riddell Meghan M Pasha Ayesha A Li Mengnan M Kawamura Takuji T Brandes Ralf P RP Hirose Tomonori T Ohno Shigeo S Gerhardt Holger H Matsuda Michiyuki M Franco Claudio A CA Nakayama Masanori M

EMBO reports 20180717 9

Impaired cell polarity is a hallmark of diseased tissue. In the cardiovascular system, laminar blood flow induces endothelial planar cell polarity, represented by elongated cell shape and asymmetric distribution of intracellular organelles along the axis of blood flow. Disrupted endothelial planar polarity is considered to be pro-inflammatory, suggesting that the establishment of endothelial polarity elicits an anti-inflammatory response. However, a causative relationship between polarity and in ...[more]

PMID: 30018153

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Project description:RATIONALE:Microvascular inflammation and endothelial dysfunction secondary to unchecked activation of endothelium play a critical role in the pathophysiology of sepsis and organ failure. The intrinsic signaling mechanisms responsible for dampening excessive activation of endothelial cells are not completely understood. OBJECTIVE:To determine the central role of YAP (Yes-associated protein), the major transcriptional coactivator of the Hippo pathway, in modulating the strength and magnitude of endothelial activation and vascular inflammation. METHODS AND RESULTS:Endothelial-specific YAP knockout mice showed increased basal expression of E-selectin and ICAM (intercellular adhesion molecule)-1 in endothelial cells, a greater number of adherent neutrophils in postcapillary venules and increased neutrophil counts in bronchoalveolar lavage fluid. Lipopolysaccharide challenge of these mice augmented NF-?B (nuclear factor-?B) activation, expression of endothelial adhesion proteins, neutrophil and monocyte adhesion to cremaster muscle venules, transendothelial neutrophil migration, and lung inflammatory injury. Deletion of YAP in endothelial cells also markedly augmented the inflammatory response and cardiovascular dysfunction in a polymicrobial sepsis model induced by cecal ligation and puncture. YAP functioned by interacting with the E3 ubiquitin-protein ligase TLR (Toll-like receptor) signaling adaptor TRAF6 (tumor necrosis factor receptor-associated factor 6) to ubiquitinate TRAF6, and thus promoted TRAF6 degradation and modification resulting in inhibition of NF-?B activation. TRAF6 depletion in endothelial cells rescued the augmented inflammatory phenotype in mice with endothelial cell-specific deletion of YAP. CONCLUSIONS:YAP modulates the activation of endothelial cells and suppresses vascular inflammation through preventing TRAF6-mediated NF-?B activation and is hence essential for limiting the severity of sepsis-induced inflammation and organ failure.

Project description:BACKGROUND: The deSUMOylase SENP2 exerts athero-protective effects by inhibiting endothelial cell (EC) activation through attenuating ERK5 and p53 SUMOylation. Publicly available datasets show that SENP2 S344 is phosphorylated by Checkpoint Kinase 1 (CHK1), but the functional role remains unknown. METHODS: Mouse SENP2 S343A (human S344A) phosphodeficient knock in (KI) mutant was generated by CRISPR/Cas9, and vascular-specific function was assessed via bone marrow transplantation (BMT). ECs from KI and wild type (WT) mice were exposed to smooth (laminar flow; l-flow) or grooved (disturbed flow; d-flow) cone-and-plate devices and characterized by RNA sequencing (RNA-seq). RESULTS: L-flow increased CHK1 S280 and SENP2 S344 phosphorylation, which inhibited ERK5 and p53 SUMOylation and atherogenesis in vivo. BMT-generated vascular specific SENP2 S344A KI showed more atherogenesis but thinner fibrous cap formation specifically in the aortic arch area (d-flow) compared to that of WT mice. Ionizing radiation (IR) decreased CHK1 expression and SENP2 S344 phosphorylation, which might account for differences between systemic and BMT-generated vascular specific SENP2 S344A KI models. RNA-seq data analysis showed that SENP2 S344 phosphorylation in ECs in response to l-flow inhibited EC activation and fibrotic changes without interfering EC lineage phenotype. Lastly, l-flow-induced expression of genes was regulated by SENP2 S344 phosphorylation through ERK5 activation and inhibited EC apoptosis. CONCLUSIONS: We uncovered a novel mechanism by which l-flow inhibits EC activation, including proliferation, migration, inflammation, and fibrotic changes, via upregulating CHK1-mediated SENP2 S344 phosphorylation to attenuate atherogenesis. We also uncovered a unique expression pattern of fibrotic changes without affecting EC lineage, which is distinct from endothelial-to-mesenchymal transition and therefore should be considered a unique type of EC activation for its potential role in vulnerable plaque formation.

Dataset Information

PAR-3 controls endothelial planar polarity and vascular inflammation under laminar flow.

Publications

PAR-3 controls endothelial planar polarity and vascular inflammation under laminar flow.

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