Activated protein C prevents inflammation yet stimulates angiogenesis to promote cutaneous wound healing.
Activated protein C (APC) is a serine protease that plays a central role in physiological anticoagulation, and has more recently been shown to be a potent anti-inflammatory mediator. Using cultured human cells, we show here that APC up-regulates the angiogenic promoters matrix metalloproteinase-2 in skin fibroblasts and umbilical vein endothelial cells, vascular endothelial growth factor in keratinocytes and fibroblasts, and monocyte chemoattractant protein-1 in fibroblasts. In the chick embryo chorioallantoic membrane assay, APC promoted the granulation/remodeling phases of wound healing by markedly stimulating angiogenesis as well as promoting reepithelialization. In a full-thickness rat skin-healing model, a single topical application of APC enhanced wound healing compared to saline control. APC-treated wounds had markedly more blood vessels on day 7 and a significantly lower infiltration of neutrophils at days 4 and 7. The broad spectrum matrix metallo-proteinase, GM6001, prevented the ability of APC to promote wound healing. In summary, our results show that APC promotes cutaneous wound healing via a complex mechanism involving stimulation of angiogenesis and inhibition of inflammation. These unique properties of APC make it an attractive therapeutic agent to promote the healing of chronic wounds.
Jackson
Christopher J
CJ
The Sutton Arthritis Research Laboratories, Institute of Bone and Joint Research, University of Sydney, Sydney, New South Wales, Australia. cjackson@med.usyd.edu.au
Xue
Meilang
M
Thompson
Patrick
P
Davey
Ross A
RA
Whitmont
Kaley
K
Smith
Susan
S
Buisson-Legendre
Nathalie
N
Sztynda
Tamara
T
Furphy
Louise J
LJ
Cooper
Alan
A
Sambrook
Philip
P
March
Lyn
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D006801:Humans; D007249:Inflammation / Q000276:immunology; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011486:Protein C / Q000494:pharmacology*; D051381:Rats; D012867:Skin / Q000187:drug effects* / Q000276:immunology; D014945:Wound Healing / Q000187:drug effects* / Q000276:immunology
D011486:Protein C; D020778:Matrix Metalloproteinase 2