Display of Cell Surface Sites for Fibronectin Assembly Is Modulated by Cell Adherence to 1F3 and C-Terminal Modules of Fibronectin

BACKGROUND: Fibronectin-null cells assemble soluble fibronectin shortly after adherence to a substrate coated with intact fibronectin but not when adherent to the cell-binding domain of fibronectin (modules (7)F3-(10)F3). Interactions of adherent cells with regions of adsorbed fibronectin other than modules (7)F3-(10)F3, therefore, are required for early display of the cell surface sites that initiate and direct fibronectin assembly. METHODOLOGY/PRINCIPAL FINDINGS: To identify these regions, coatings of proteolytically derived or recombinant pieces of fibronectin containing modules in addition to (7)F3-(10)F3 were tested for effects on fibronectin assembly by adherent fibronectin-null fibroblasts. Pieces as large as one comprising modules (2)F3-(14)F3, which include the heparin-binding and cell adhesion domains, were not effective in supporting fibronectin assembly. Addition of module (1)F3 or the C-terminal modules to modules (2)F3-(14)F3 resulted in some activity, and addition of both (1)F3 and the C-terminal modules resulted in a construct, (1)F3-C, that best mimicked the activity of a coating of intact fibronectin. Constructs (1)F3-C V0, (1)F3-C V64, and (1)F3-C Delta(V(15)F3(10)F1) were all able to support fibronectin assembly, suggesting that (1)F3 through (11)F1 and/or (12)F1 were important for activity. Coatings in which the active parts of (1)F3-C were present in different proteins were much less active than intact (1)F3-C. CONCLUSIONS: These results suggest that (1)F3 acts together with C-terminal modules to induce display of fibronectin assembly sites on adherent cells

N-cadherin Cell-Cell Adhesion Complexes Are Regulated by Fibronectin Matrix Assembly*

Fibronectin is a principal component of the extracellular matrix. Soluble fibronectin molecules are assembled into the extracellular matrix as insoluble, fibrillar strands via a cell-dependent process. In turn, the interaction of cells with the extracellular matrix form of fibronectin stimulates cell functions critical for tissue repair. Cross-talk between cell-cell and cell-extracellular matrix adhesion complexes is essential for the organization of cells into complex, functional tissue during embryonic development and tissue remodeling. Here, we demonstrate that fibronectin matrix assembly affects the organization, composition, and function of N-cadherin-based adherens junctions. Using fibronectin-null mouse embryonic myofibroblasts, we identified a novel quaternary complex composed of N-cadherin, β-catenin, tensin, and actin that exists in the absence of a fibronectin matrix. In the absence of fibronectin, homophilic N-cadherin ligation recruited both tensin and α5β1 integrins into nascent cell-cell adhesions. Initiation of fibronectin matrix assembly disrupted the association of tensin and actin with N-cadherin, released α5β1 integrins and tensin from cell-cell contacts, stimulated N-cadherin reorganization into thin cellular protrusions, and decreased N-cadherin adhesion. Fibronectin matrix assembly has been shown to recruit α5β1 integrins and tensin into fibrillar adhesions. Taken together, these studies suggest that tensin serves as a common cytoskeletal link for integrin- and cadherin-based adhesions and that the translocation of α5β1 integrins from cell-cell contacts into fibrillar adhesions during fibronectin matrix assembly is a novel mechanism by which cell-cell and cell-matrix adhesions are coordinated

Dolichoectasia—an evolving arterial disease

Dolichoectasia is an arterial disease that causes dilatation and/or tortuosity of the affected vessel. The prevalence of dolichoectasia increases with age, and this disease is also associated with other traditional cardiovascular risk factors. Multiple pathophysiological processes might lead to the development of dolichoectatic vessels, and activation of metalloproteinases and irregular turbulent blood flow seem to cause irreversible disruption of the internal elastic lamina. Intracranial dolichoectasia commonly presents with ischemic or hemorrhagic stroke, and/or cranial neuropathies. The posterior circulation is more frequently affected by the dolichoectatic process than the anterior circulation. A positive diagnosis of dolichoectasia requires visual assessment of vessel shape and, if the posterior circulation is affected, application of Smoker's criteria. Reproducible criteria that aid diagnosis of dolichoectasia in the anterior circulation are lacking. No specific treatment for dolichoectasia exists, and the surgical and medical therapies that have been used to treat this condition have not been systematically evaluated. More evidence is needed to better understand the underlying dilatatory artheriopathy that causes this disease, and to determine whether patients with dolichoectasia might benefit from early diagnosis. In this article, we provide a comprehensive review of current knowledge regarding dolichoectasia, and highlight gaps in our knowledge to aid future research

Vascular Stenosis: An Introduction

International audienceAn arterial stenosis is a narrowing of the lumen that disturbs the local blood flow and precludes the adequate irrigation of perfused organs. A vascular stenosis can be extrinsic, which is caused by external compression (e.g., aneurysms and tumors), or intrinsic, currently related to atherosclerosis.Atherosclerosis is defined by an intramural retention of lipids coupled to inflammation and dyslipidemia. Atherosclerosis scatters throughout large and medium thick-walled systemic arteries, especially near and in branching regions. (Pulmonary arterial stenosis is a congenital defect.)Atherosclerosis is characterized by migration from the media, proliferation, and dedifferentiation of vascular smooth myocytes in the subendothelial layer, in addition to monocyte diapedesis and differentiation into macrophages. Both smooth myocytes and macrophages scavenge accumulated oxidized low-density lipoproteins (oxLDL) and transform into foam cells. Atherosclerosis produces symptoms when the arterial lumen is severely narrowed.Advanced atherosclerotic plaques can be destabilized, thereby being a source of clotting and subsequent emboli. Emboli block tissue perfusion in a smaller downstream artery, thereby causing ischemia and infarction.The treatment of stenotic arterial segments relies on surgical grafting or medical minimally invasive procedures such as stenting. However, both methods often lead to intimal hyperplasia resulting from uncontrolled proliferation of vascular smooth myocytes. Whereas atheroma evolves during a time magnitude order of 10 years, posttherapeutic intimal hyperplasia develops in a period of order 1 month.Successful stenting can be assumed as a procedure without strong endothelial injury. In other words, both delayed thrombosis and intimal hyperplasia result from stent deployment that more or less severely damages the vascular endothelium. To eliminate these complications, drug-eluting stents have been designed and fabricated. However, the antiproliferative drug not only blocks vascular smooth myocyte division but also precludes endothelium healing. In the absence of proper endothelial interface between blood and arterial wall, that is, when the local controller of blood coagulation and cell proliferation is missing, thrombosis and restenosis occur.Arterial stenoses have stimulated biomechanicians and applied mathematicians. They carried out flow visualization and pressure and velocity measurements in experimental models of stenoses with idealized, symmetrical or not, geometry. In parallel to technological improvements of medical imaging techniques, computational fluid dynamics, due to new numerical schemes and high-performance computing, enables to perform numerical tests on subject-specific compartments of the blood circulation, after 3D reconstruction, rather than focusing on more or less short arterial, branched or not, segments. In addition, the drug release from drug-eluting stents is investigated using mathematical models