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J Biol Chem, Vol. 273, Issue 46, 30719-30728, November 13, 1998

Endothelial Cell VE-cadherin Functions as a Receptor for the 15-42 Sequence of Fibrin

From the Cardeza Foundation for Hematologic Research and Division of Hematology, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107

The contact of fibrin with the apical surface of human umbilical vein endothelial cells (HUVEC) can induce capillary tube formation via the interaction of fibrin 15-42 with a putative cell receptor (Chalupowicz, D. G., Chowdhury, Z. A., Bach, T. L., Barsigian, C., and Martinez, J. (1995) J. Cell Biol. 130, 207-215). To characterize this interaction, we studied the binding of the thrombin-cleaved N-terminal disulfide knot of fibrin (NDSK II), a dimeric fragment with exposed 15-42, to HUVEC in three separate assay systems. Time-course binding of ¹²⁵I-NDSK II to HUVEC monolayers or suspensions revealed that binding was specific at 50-60%, as determined by the addition of unlabeled NDSK II. Specific binding of ¹²⁵I-NDSK II to HUVEC was 70% reversible by dilution or by competition, and was found to be divalent cation-independent. Binding plateaued after 10 min at a saturation of 15-20 nM. Scatchard analysis using the LIGAND computer program defined a single population of receptors with a K_D of 7.7 ± 1.6 nM and approximately 21,000 ± 7000 binding sites/cell. N-terminal disulfide knot derivatives in which 15-42 was absent (NDSK 325) or unexposed (NDSK, NDSK I) did not show specific binding. Specific binding of ¹²⁵I-NDSK II could not be inhibited by RGDS or by antibodies to the _v3 or ₁ integrins, PECAM-1, ICAM-1, or N-cadherin. In contrast, a synthetic 15-42/ovalbumin conjugate inhibited total ¹²⁵I-NDSK II binding by 47 ± 19% (corresponding to 95% of specific ¹²⁵I-NDSK II bound) and a monoclonal antibody to vascular endothelial cadherin (VE-cadherin) inhibited binding by 35 ± 8% (corresponding to 70% of specific ¹²⁵I-NDSK II bound). Another assay was based on the capture of cadherins from HUVEC lysates by a polyclonal pan-cadherin antibody immobilized on plastic dishes. Binding of NDSK II to the captured cadherins was 89 ± 5% specific, while specific binding of NDSK 325 and NDSK was negligible. An immortalized line of human adipose-derived microvascular endothelial cells, which express N-cadherin but not VE-cadherin, demonstrated no specific binding of NDSK II by the capture assay. These data define a novel interaction of fibrin with VE-cadherin, which is mediated by the fibrin N-terminal 15-42 sequence, and may contribute to the mechanism through which fibrin induces angiogenesis.

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