Homocysteine inhibits neoangiogenesis in mice through blockade of annexin A2-dependent fibrinolysis.
When plasma levels of homocysteine (HC), a thiol amino acid formed upon methionine demethylation, exceed 12 muM, individuals are at increased risk of developing large vessel atherothrombosis and small vessel dysfunction. The annexin A2 complex (termed "A2") is the cell surface coreceptor for plasminogen and TPA and accelerates the catalytic activation of plasmin, the major fibrinolytic agent in mammals. We previously showed that HC prevents A2-mediated, TPA-dependent activation of plasminogen in vitro by disulfide derivatization of the "tail" domain of A2. We also demonstrated that fibrinolysis and angiogenesis are severely impaired in A2-deficient mice. We now report here that, although hyperhomocysteinemic mice had a normal coagulation profile and normal platelet function, fibrin accumulated in their tissues due to reduced perivascular fibrinolytic activity and angiogenesis was impaired. A2 isolated from hyperhomocysteinemic mice failed to fully support TPA-dependent plasmin activation. However, infusion of hyperhomocysteinemic mice with fresh recombinant A2, which localized to neoangiogenic endothelial cells, resulted in normalization of angiogenesis and disappearance of peri- and intravascular fibrin. We therefore conclude that hyperhomocysteinemia impairs postnatal angiogenesis by derivatizing A2, preventing perivascular fibrinolysis, and inhibiting directed endothelial cell migration. These findings provide a mechanistic explanation for microvascular dysfunction and macrovascular occlusion in individuals with hyperhomocysteinemia.
Jacovina
Andrew T
AT
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA.
Deora
Arunkumar B
AB
Ling
Qi
Q
Broekman
M Johan
MJ
Almeida
Dena
D
Greenberg
Caroline B
CB
Marcus
Aaron J
AJ
Smith
Jonathan D
JD
Hajjar
Katherine A
KA
D000818:Animals; D017306:Annexin A2 / Q000378:metabolism* / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects; D016510:Corneal Neovascularization / Q000503:physiopathology; D004032:Diet; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D006710:Homocysteine / Q000378:metabolism* / Q000494:pharmacology; D020138:Hyperhomocysteinemia / Q000503:physiopathology; D008297:Male; D008715:Methionine / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology
D017306:Annexin A2; D011994:Recombinant Proteins; D006710:Homocysteine; D005337:Fibrin; D008715:Methionine