ORCID Profile
0000-0003-0782-9957
Current Organisation
University of Oslo
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Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2004
DOI: 10.1161/01.ATV.0000146529.68729.8B
Abstract: Objective— The leukocyte integrin Mac-1 (α M β 2 , CD11b/CD18) binds a number of ligands and counter-receptors and thereby is a major determinant in regulation of leukocyte adhesion and extravasation. Vitronectin (VN) is an adhesion-promoting factor that is abundantly present as matrix molecule in vascular diseases such as atherosclerosis. Until now, only an indirect interaction between Mac-1 and VN via the urokinase receptor (urokinase plasminogen activator receptor) was known. We now propose that Mac-1 and VN can directly interact with each other. Methods and Results— In an in vitro system with purified components, Mac-1 specifically bound the multimeric matrix form of VN but not the monomeric plasma form. Using various competitors, the interaction domains in Mac-1 and VN were localized. Mac-1–expressing but not untransfected Chinese hamster ovary cells adhered strongly on VN. Introduction of a GFFKR deletion in the α M subunit of Mac-1, which increases the constitutive activation of the integrin, led to increased adhesion on VN. Peripheral human blood neutrophils adhered and migrated on multimeric VN in a Mac-1–dependent manner. Conclusions— These results show that there is a specific integrin-affinity–regulated interaction between Mac-1 and the matrix form but not the plasma form of VN that may significantly participate in leukocyte adhesion and extravasation.
Publisher: Elsevier BV
Date: 08-2016
DOI: 10.1016/J.CELREP.2016.07.040
Abstract: The body has the capacity to compensate for an occluded artery by creating a natural bypass upon increased fluid shear stress. How this mechanical force is translated into collateral artery growth (arteriogenesis) is unresolved. We show that extravasation of neutrophils mediated by the platelet receptor GPIbα and uPA results in Nox2-derived reactive oxygen radicals, which activate perivascular mast cells. These c-kit(+)/CXCR-4(+) cells stimulate arteriogenesis by recruiting additional neutrophils as well as growth-promoting monocytes and T cells. Additionally, mast cells may directly contribute to vascular remodeling and vascular cell proliferation through increased MMP activity and by supplying growth-promoting factors. Boosting mast cell recruitment and activation effectively promotes arteriogenesis, thereby protecting tissue from severe ischemic damage. We thus find that perivascular mast cells are central regulators of shear stress-induced arteriogenesis by orchestrating leukocyte function and growth factor/cytokine release, thus providing a therapeutic target for treatment of vascular occlusive diseases.
Publisher: American Society of Hematology
Date: 15-11-2002
DOI: 10.1182/BLOOD-2002-03-0778
Abstract: The urokinase receptor (urokinase plasminogen activator receptor uPAR) regulates monocyte adhesion by direct binding to vitronectin and by forming complexes with integrins. Therefore, possible up-regulation of uPAR in acute myocardial infarction (AMI) may affect monocyte adhesion. In 20 patients with AMI, uPAR surface expression (measured by flow cytometry) was increased compared with that in patients with chronic stable angina (mean ± SD fluorescence, 179 ± 96 vs 80 ± 53 P = .002). Expression of uPAR correlated with activation of β2-integrins lymphocyte function–associated antigen 1 (LFA-1) and macrophage antigen 1 (Mac-1), measured by using monoclonal antibodies (mAbs) 24 and CBRM1/5. Isolated mononuclear cells (MNCs) from patients with AMI showed enhanced adhesiveness to human umbilical vein endothelial cells (HUVECs), to fibrinogen (Mac-1 ligand), and to vitronectin (uPAR ligand). Excessive adhesion of MNCs to HUVECs was inhibited by mAbs anti-CD18 (84%), anti-CD11a (51%), and anti-CD11b (57%), indicating a major contribution of LFA-1 and Mac-1. The mAb anti-uPAR R3 blocked adhesion of cells from patients with AMI to vitronectin (95%) but also β2-integrin–mediated adhesion to fibrinogen (79%) and HUVECs (66%). Incubation of monocytic MonoMac6 cells with plasma from patients with AMI enhanced uPAR messenger RNA expression and cell adhesion to HUVECs. Thus, released soluble factors may contribute to enhanced monocyte adhesion in AMI. Mouse pre-B lymphocytes (BAF3 cells) transfected with various amounts of uPAR complementary DNA showed a strong correlation of uPAR expression with β2-integrin–dependent adhesion to intercellular adhesion molecule 1, thus providing evidence for the functional relevance of uPAR up-regulation in an isolated in vitro system. In conclusion, we found that uPAR expression is elevated on monocytes in AMI and contributes to enhanced cell adhesion. Thus, uPAR may be a novel target for prevention of unwanted monocyte recruitment as part of inflammatory cardiovascular processes.
Publisher: Public Library of Science (PLoS)
Date: 11-2018
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Sandip Kanse.