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Endogenous protein C is essential for the functional integrity of human endothelial cells

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Abstract

Circulating protein C (PC) plays a vital role as an anti-coagulant and anti-inflammatory mediator. We show here that human endothelial cells produce PC that acts through novel mediators to enhance their own functional integrity. When endogenous PC or its receptor, endothelial protein C receptor (EPCR), was suppressed by small interfering (si) RNA, human umbilical cord endothelial cell (HUVEC) proliferation was decreased and apoptosis elevated. Interestingly, PC or EPCR siRNA significantly increased HUVEC permeability, which is likely via reduction of the angiopoietin (Ang)1/Ang2 ratio and inhibition of the peripheral localization of the tight junction protein, zona occludins-1. In addition, PC or EPCR siRNA inhibited type IV collagen and matrix metalloproteinase-2, providing the first evidence that PC contributes to vascular basement membrane formation. These newly described actions of endogenous PC act to stabilize endothelial cells and enhance barrier function, to potentially promote the functional integrity of blood vessels.

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Abbreviations

APC:

Activated protein C

EPCR:

Endothelial protein C receptor

HUVEC:

Human umbilical cord endothelial cells

MMP:

Matrix metalloproteinase

siRNA:

Small interfering RNA

ZO-1:

Zonula occludens-1

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Acknowledgments

This work was largely supported by NHMRC Career Development Award and NHMRC project grant. We wish to thank the Maternity Unit at Royal North Shore Hospital for providing umbilical cords and the Rebecca Cooper Foundation and Isabelle Millner and family for financial support.

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Authors and Affiliations

  1. Sutton Research Laboratories, Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney at Royal North Shore Hospital, Level 10, The Kolling Building, St Leonards, NSW, 2065, Australia

    Meilang Xue, Nikita Minhas, Shu-Oi Chow, Suat Dervish & Christopher J. Jackson

  2. Department of Rheumatology, Institute of Bone and Joint Research, Kolling Institute of Medical Research, The University of Sydney at Royal North Shore Hospital, St Leonards, NSW, 2065, Australia

    Philip N. Sambrook & Lyn March

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  1. Meilang Xue
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  2. Nikita Minhas
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Correspondence to Meilang Xue.

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Xue, M., Minhas, N., Chow, SO. et al. Endogenous protein C is essential for the functional integrity of human endothelial cells. Cell. Mol. Life Sci. 67, 1537–1546 (2010). https://doi.org/10.1007/s00018-010-0269-y

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