Interaction of Fibrin with VE‐Cadherin

Abstract

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 β15–42 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.

Fibrinopeptides A and B release in the process of surface fibrin formation

“…First, the N-terminal portions of fibrin ␤ chains (amino-acid residues ␤15-42), which are exposed after cleavage of FpB, have been implicated in a number of important processes, including angiogenesis and inflammation. [39][40][41][42][43][44][45][46][47][48] Second, the released FpB is a potent chemoattractant, 42 and therefore its preferential release may indicate the physiological purpose in the attraction of cells to the site of injury.It has been shown that the association of soluble fibrinogen with the fibrin clot results in the reduced adhesiveness of such fibrinogenfibrin matrices toward leukocytes and platelets. 49,50 Our finding that FpA is less accessible for thrombin in surface-bound fibrinogenfibrin complexes may be interpreted as a novel supplementary mechanism preventing the rapid conversion of bound fibrinogen into fibrin, thereby extending its anti-adhesive properties and providing an additional level of protection of thrombi from premature dissolution.…”

“…First, the N-terminal portions of fibrin ␤ chains (amino-acid residues ␤15-42), which are exposed after cleavage of FpB, have been implicated in a number of important processes, including angiogenesis and inflammation. [39][40][41][42][43][44][45][46][47][48] Second, the released FpB is a potent chemoattractant, 42 and therefore its preferential release may indicate the physiological purpose in the attraction of cells to the site of injury.…”

Reactive carbonyl compounds (RCCs) cause aggregation and dysfunction of fibrinogen

“…Fibrinogen also plays a role in the initiation of angiogenesis (Chalupowicz et. al., 1995;Martinez et. al., 2001), and the propagation of infection.…”

The Role of Fibrin(ogen) in Transendothelial Cell Migration During Breast Cancer Metastasis

“…Thus, the innate immune response is activated to defend the host against this neoplastic insult. Release of IL-6 systemically leads to increased production of plasma Fg and fibrin formation resulting in exposure of  15-42 and binding to VE-cadherin, a step critical for angiogenesis (Bach et al, 1998b;Martinez et al, 2001). Furthermore, VEGF binds to Fg and fibrin with high affinity (Sahni & Francis, 2000), which may be necessary for Fg to enhance VEGF-mediated endothelial cell permeability without potentiating endothelial cell proliferation.…”