Abstract/Details

Identification of a novel interaction between the N-terminal domain of fibrin and VE-cadherin: Its role in angiogenesis


1998 1998

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Abstract (summary)

Angiogenesis can be conceptually separated into four basic steps which are (1) cell-mediated, proteolytic degradation of the basement membrane, (2) migration of endothelial cells out of the vessel, (3) proliferation of cells in the extracellular space, and (4) morphogenesis of the cells into tube-like structures commonly referred to as "capillary tubes." The role of the matrix in orchestrating angiogenesis is complex and the cellular events induced by extracellular matrix proteins such as, collagen, fibrin, fibronectin, or laminin are unknown. The purpose of this investigation was to examine the biochemical interaction between fibrin and the endothelial cell and to develop an in vitro system to analyze the effect of this interaction on the induction of capillary-like tubes.

The first part of this thesis aimed to develop a simplified assay system to study the involvement of fibrin in the final step of angiogenesis. We demonstrated that when human umbilical vein endothelial cell monolayers are sandwiched between two fibrin gels under serum-free conditions, they rearrange into an extensive net of capillary tubes within 5 hours and remain intact from 1 to 3 days. This system presumably mimics the last stage of angiogenesis. The interaction of the apical surface of the monolayer with fibrin II, which exposes an N-terminal sequence of its $\beta$-chain ($\beta$15-42), was found to be fundamental in this process.

The second part of this thesis examined the importance of cell adhesion molecules in the angiogenic process. We utilized the same model in which endothelial cell monolayers, sandwiched between two fibrin II or two collagen I gels, are induced to form capillary-like tubes. We observed that a monoclonal antibody directed against a region within the first and second extracellular domains of vascular endothelial cadherin (VE-cadherin), inhibits both the formation and maintenance of the capillary tubes. In contrast, monoclonal antibodies directed against N-cadherin, the $\rm\alpha\sb{v}\beta\sb3$ integrin, as well as PECAM-1 do not inhibit tube formation. Moreover, there appeared to be no quantitative difference in VE-cadherin transcription or translation during the differentiation process, and immunocytochemical studies revealed that VE-cadherin is concentrated at intercellular junctions, just as it is in monolayers, in multicellular capillary tubes.

The final part of this thesis demonstrated through biochemical studies, such as binding, immunoprecipitation, and antigen capture assays, that the N-terminal domain of fibrin II, via the sequence $\beta$15-42, specifically binds to human umbilical vein endothelial cells in a cation-independent manner. Furthermore, this interaction is likely mediated by VE-cadherin since a monoclonal antibody to this molecule inhibits binding, and cells devoid of VE-cadherin do not bind the N-terminus of fibrin II. (Abstract shortened by UMI.)

Indexing (details)


Subject
Pharmacology;
Oncology;
Cellular biology
Classification
0419: Pharmacology
0992: Oncology
0379: Cellular biology
Identifier / keyword
Health and environmental sciences; Biological sciences
Title
Identification of a novel interaction between the N-terminal domain of fibrin and VE-cadherin: Its role in angiogenesis
Author
Bach, Tami Lee
Number of pages
188
Publication year
1998
Degree date
1998
School code
0272
Source
DAI-B 59/04, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780591817096, 0591817098
Advisor
Martinez, Jose
University/institution
Thomas Jefferson University
University location
United States -- Pennsylvania
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
9829077
ProQuest document ID
304466840
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304466840
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