Endogenous protein C is essential for the functional integrity of human endothelial cells.
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.
Xue
Meilang
M
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@sydney.edu.au
Minhas
Nikita
N
Chow
Shu-Oi
SO
Dervish
Suat
S
Sambrook
Philip N
PN
March
Lyn
L
Jackson
Christopher J
CJ
D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D002199:Capillary Permeability / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D000074283:Endothelial Protein C Receptor; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D011486:Protein C / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
D042682:Angiopoietins; D015703:Antigens, CD; D024141:Collagen Type IV; D000074283:Endothelial Protein C Receptor; D008565:Membrane Proteins; C478370:PROCR protein, human; D010750:Phosphoproteins; D011486:Protein C; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D020778:Matrix Metalloproteinase 2