Intercellular junctions and endothelial permeability are regulated by cell chirality

Cell chirality is newly discovered as an intrinsic cell property characterized by the bias of cell polarizing along the left‐right axis. We have recently reported that the endothelial phenotype is right biased; however, little is known about its implications in vascular physiology. In this study, we measured chirality and permeability of human umbilical vein endothelial cells by utilizing micropatterning and transwell culture. Even with low‐level PKC activation, we observed a remarkable reversal of endothelial cell chirality, accompanied by a non‐monotonic change in the monolayer permeability. Using a co‐culture model and immunofluorescence‐based image analysis, we found that uniformity in cell chirality was important for endothelial barrier function such that chirality mismatch between adjacent cells resulted in disrupted cell‐cell junctions leading to increased permeability, which peaked when cell chirality was randomized in the endothelial monolayer. Pharmacological and genetic studies allowed us to determine that PKCα and PI3K/AKT mediated the switch of cell chirality, while other known vascular permeability factors such as VEGF, PAF, and histamine regulated permeability independent of cell chirality. Our study has demonstrated for the first time the role of endothelial cell chirality in vascular permeability regulation and provides unique opportunities for drug delivery across tightly connected cellular sheets. Support or Funding Information This work was supported by the National Institutes of Health (OD/NICHD DP2HD083961), National Science Foundation (CAREER CMMI‐1254656), American Heart Association (13SDG17230047), March of Dimes (MOD 5‐FY14‐111). Leo Q. Wan is a Pew Scholar in Biomedical Sciences (PEW 00026185), supported by the Pew Charitable Trusts. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .