PAR‐3 controls endothelial planar polarity and vascular inflammation under laminar flow |
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| Authors: | Takao Hikita Fatemeh Mirzapourshafiyi Pedro Barbacena Meghan Riddell Ayesha Pasha Mengnan Li Takuji Kawamura Ralf P Brandes Tomonori Hirose Shigeo Ohno Holger Gerhardt Michiyuki Matsuda Claudio A Franco Masanori Nakayama |
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| Affiliation: | 1. Laboratory for Cell Polarity and Organogenesis, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany;2. Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal;3. Institute for Cardiovascular Physiology, Goethe University, Frankfurt am Main, Germany;4. Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, Yokohama, Japan;5. Integrative Vascular Biology Laboratory, Max‐Delbrück‐Center for Molecular Medicine, Berlin, Germany;6. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan |
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| 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 GSK3β activity in response to laminar blood flow. We show that flow‐induced spatial distribution of PAR‐3/aPKCλ and aPKCλ/GSK3β complexes controls local GSK3β activity and thereby regulates endothelial planar polarity. The spatial information for GSK3β 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. |
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| Keywords: | atherosclerosis cell polarity endothelial cell flow PAR‐3 |
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