Interaction of fibrin with VE-cadherin.
The conversion of fibrinogen into fibrin and the association of fibrin(ogen) with activated platelets play a fundamental role in hemostasis because their interaction with the injured vessel prevents blood extravasation. Platelet aggregates and fibrin also participate in the occlusion of the vascular lumen in pathological conditions. Fibrin II also promotes the formation of new blood vessels, for example, during wound healing and tumor growth. Using an in vitro assay, we have studied the mechanism by which fibrin II induces formation of capillaries. Generation of fibrin II on top of an endothelial cell monolayer rapidly rearranged the ECs into a capillary network. In contrast, neither fibrin I nor fibrin 325 induced these morphogenetic changes, indicating that exposure of the N-terminal peptide beta 15-42 is involved in this process. Binding studies, using the N-terminal fragment of fibrin (NDSK II), showed that NDSK II binds to EC with high affinity, but neither NDSK nor NDSK325 bound specifically. Binding of NDSK II to endothelial cells was blocked with an antibody to VE-cadherin. Direct association of NDSK II and VE-cadherin was also demonstrated in a VE-cadherin antibody capture assay. NDSK II bound specifically with the captured VE-cadherin but NDSK or NDSK 325 did not associate with VE-cadherin. Moreover, fibrin II associated with EC VE-cadherin and this interaction triggered the formation of capillary-like structures. A better understanding of the cellular responses to fibrin, identification of the fibrin binding site within VE-cadherin and the intracellular signaling that follows this interaction, could yield important information that may translate into better control of the angiogenic process.
Martinez
J
J
Cardeza Foundation for Hematologic Research, Jefferson Medical College of Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA 19107-5099, USA. Jose.Martinez@mail.tju.edu
Ferber
A
A
Bach
T L
TL
Yaen
C H
CH
D015703:Antigens, CD; D001665:Binding Sites; D015820:Cadherins / Q000378:metabolism*; D002196:Capillaries / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D005337:Fibrin / Q000378:metabolism*; D006801:Humans; D008854:Microscopy, Electron; D011485:Protein Binding; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D005337:Fibrin; D000099152:Cadherin 5