Temporal exposure of cryptic collagen epitopes within ischemic muscle during hindlimb reperfusion.
Chronic limb-threatening ischemia is a devastating disease with limited surgical options. However, inducing controlled angiogenesis and enhancing reperfusion holds therapeutic promise. To gain a better understanding of the mechanisms that contribute to limb reperfusion, we examined the temporal biochemical and structural changes occurring within the extracellular matrix of ischemic skeletal muscle. Both the latent and active forms of MMP-2 and -9 significantly increased during the active phase of limb reperfusion. Moreover, small but significant alterations in tissue inhibitors of metalloproteinase levels also occurred during a similar time course, consistent with a net increase in extracellular matrix remodeling. This temporal increase in MMP activity coincided with enhanced exposure of the unique HU177 cryptic collagen epitope. Although the HUIV26 cryptic collagen epitope has been implicated in angiogenesis, little is known concerning such epitopes within ischemic muscle tissue. Here, we provide the first evidence that a functionally distinct cryptic collagen epitope (HU177) is temporally exposed in ischemic muscle tissue during the active phase of reperfusion. Interestingly, the exposure of the HU177 epitope was greatly diminished in MMP-9 null mice, corresponding with significantly reduced limb reperfusion. Therefore, the regulated exposure of a unique cryptic collagen epitope within ischemic muscle suggests an important role for collagen remodeling during the active phase of ischemic limb reperfusion.
Gagne
Paul J
PJ
New York University School of Medicine, Department of Surgery, 530 First Avenue, Suite 6F, New York, NY 10016, USA. paul.gagne@med.nyu.edu
Tihonov
Nikita
N
Li
Xialou
X
Glaser
Joseph
J
Qiao
Jhenrong
J
Silberstein
Michael
M
Yee
Herman
H
Gagne
Elizabeth
E
Brooks
Peter
P
D000818:Animals; D003094:Collagen / Q000737:chemistry* / Q000276:immunology / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000032:analysis / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply*; D007150:Immunohistochemistry; D007511:Ischemia / Q000378:metabolism*; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000737:chemistry*; D015424:Reperfusion; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000032:analysis; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis
D000939:Epitopes; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9