Antiangiogenic plasma activity in patients with systemic sclerosis.
OBJECTIVE
Systemic sclerosis (SSc; scleroderma) is a systemic connective tissue disease with an extensive vascular component that includes aberrant microvasculature and impaired wound healing. The aim of this study was to investigate the presence of antiangiogenic factors in patients with SSc.


METHODS
Plasma samples were obtained from 30 patients with SSc and from 10 control patients without SSc. The samples were analyzed for the ability of plasma to affect endothelial cell migration and vascular structure formation and for the presence of antiangiogenic activity.


RESULTS
Exposure of normal human microvascular dermal endothelial cells to plasma from patients with SSc resulted in decreased cell migration (mean +/- SEM 52 +/- 5%) and tube formation (34 +/- 6%) compared with that in plasma from control patients (P < 0.001 for both). SSc plasma contained 2.9-fold more plasminogen kringle 1-3 fragments (angiostatin) than that in control plasma. The addition of angiostatin to control plasma resulted in inhibition of endothelial cell migration and proliferation similar to that observed in SSc plasma. In vitro studies demonstrated that granzyme B and other proteases contained in T cell granule content cleave plasminogen and plasmin into angiostatin fragments.


CONCLUSIONS
Plasminogen conformation in patients with SSc enables granzyme B and granule content protease to limit the proangiogenic effects of plasmin and increase the levels of antiangiogenic angiostatin. This increase in angiostatin production may account for some of the vascular defects observed in patients with SSc.
Mulligan-Kehoe
Mary Jo
MJ
Angiogenesis Research Center, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
Drinane
Mary C
MC
Mollmark
Jessica
J
Casciola-Rosen
Livia
L
Hummers
Laura K
LK
Hall
Amy
A
Rosen
Antony
A
Wigley
Fredrick M
FM
Simons
Michael
M
D000328:Adult; D020533:Angiogenesis Inhibitors / Q000097:blood / Q000378:metabolism*; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000097:blood / Q000503:physiopathology*; D014945:Wound Healing / Q000502:physiology
D020533:Angiogenesis Inhibitors; D053804:Granzymes