Protein disulfide isomerase capture during thrombus formation in vivo depends on the presence of β3 integrins.
Extracellular protein disulfide isomerase (PDI) is required for platelet thrombus formation and fibrin generation after arteriolar wall injury in live mice. PDI is secreted from platelets and endothelial cells on cellular activation, but the mechanism of capture of secreted PDI within the injured vasculature is unknown. We establish that, like the endothelial β3 integrin α(V)β(3), the platelet integrin α(IIb)β(3) binds PDI. PDI also binds to recombinant β3. Using intravital microscopy, we demonstrate that PDI accumulation at the site of laser-induced arteriolar wall injury is markedly reduced in β3-null (β3(-/-)) mice, and neither a platelet thrombus nor fibrin is generated at the vessel injury site. The absence of fibrin after vascular injury in β3(-/-) mice is because of the absence of extracellular PDI. To evaluate the relative importance of endothelial α(V)β(3) versus platelet α(IIb)β(3) or α(V)β(3), we performed reciprocal bone marrow transplants on wild-type and β3(-/-) mice. PDI accumulation and platelet thrombus formation were markedly decreased after vessel injury in wild-type mice transplanted with β3(-/-) bone marrow or in β3(-/-) mice transplanted with wild-type bone marrow. These results indicate that both endothelial and platelet β3 integrins contribute to extracellular PDI binding at the vascular injury site.
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Jaehyung
J
Cho
Daniel R
DR
Kennedy
Lin
L
Lin
Mingdong
M
Huang
Glenn
G
Merrill-Skoloff
Barbara C
BC
Furie
Bruce
B
Furie
D000818:Animals; D001160:Arterioles / Q000201:enzymology / Q000293:injuries; D001777:Blood Coagulation / Q000502:physiology; D001792:Blood Platelets / Q000201:enzymology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D016466:CHO Cells; D006224:Cricetinae; D042783:Endothelial Cells / Q000201:enzymology*; D005110:Extracellular Space / Q000201:enzymology; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018715:Microscopy, Video; D018482:Muscle, Skeletal / Q000098:blood supply; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D013927:Thrombosis / Q000378:metabolism*; D018183:Transplantation Chimera
D039302:Integrin alphaVbeta3; D039661:Integrin beta3; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019704:Protein Disulfide-Isomerases