Biomedical subjects

Marlies E J Reinders

Publications and source records attributed to Marlies E J Reinders.

5 recordsLinked to original sources

PubMed2006

Vascular endothelial growth factor-induced signaling pathways in endothelial cells that mediate overexpression of the chemokine IFN-gamma-inducible protein of 10 kDa in vitro and in vivo.

Vascular endothelial growth factor (VEGF), an angiogenesis factor, has recently been found to have potent proinflammatory properties in vivo. However, the mechanism by which it mediates inflammation is poorly understood. In this study, we have evaluated the function of VEGF on the induced expression and function of the T cell chemoattractant chemokine IFN-gamma-inducible protein of 10 kDa (IP-10). In vitro, we find that VEGF augments the effect of IFN-gamma on the induction of IP-10 mRNA and protein expression in endothelial cells. Moreover, we show that VEGF and IFN-gamma regulate the activation of the IP-10 promoter, and that the kinases PI3K, phosphoinositide-dependent kinase 1, and Akt act as intermediary signaling molecules for cytokine-inducible IP-10 transcriptional activation in endothelial cells. To examine whether VEGF is functional for IP-10 expression in vivo, Chinese hamster ovary cells that were designed to secrete VEGF were injected s.c. into the skin of nude mice and were found to mediate a time-dependent increase in IP-10 mRNA. This response was reduced in animals treated systemically with the PI3K inhibitor wortmannin. When the Chinese hamster ovary cells expressing VEGF plasmid were injected s.c. into C57BL/6 wild-type or CXCR3-/- mice, they elicited an inflammatory reaction in wild-type but not in CXCR3-/- mice. Collectively, these findings indicate that VEGF-induced augmentation of IP-10 expression is a major mechanism underlying its proinflammatory function.

3-Phosphoinositide-Dependent Protein Kinases↗

PubMed2006

Angiogenesis and endothelial cell repair in renal disease and allograft rejection.

This review discusses the concept that the turnover and replacement of endothelial cells is a major mechanism in the maintenance of vascular integrity within the kidney. CD133+CD34+KDR+ endothelial cell progenitor cells emigrate from the bone marrow and differentiate into CD34+KDR+ expressing cells, which are present in high numbers within the circulation. These progenitor cells are available for recruitment into normal or inflamed tissues to facilitate endothelial cell repair. In several forms of renal disease, proinflammatory insults mediate oxidative stress, senescence, and sloughing of endothelial cells. A lack of growth factors or an inefficient recruitment of endothelial cell progenitors results in hypoxic tissue injury and accelerates the process of chronic renal failure. Augmentation of vascular repair by the provision of growth factors such as vascular endothelial growth factor or by the transfer of progenitor cells directly into the kidney can be protective and prevent ongoing interstitial damage. In allografts, persistent injury results in excessive turnover of graft vascular endothelial cells. Moreover, chronic damage elicits a response that is associated with the recruitment of both leukocytes and endothelial cell progenitors, facilitating an overlapping process of inflammation and angiogenesis. Because the angiogenesis reaction itself is proinflammatory, this process becomes self-sustaining. Collectively, these data indicate that angiogenesis and endothelial cell turnover are important in renal inflammatory processes and allograft rejection. Manipulation of the response may have therapeutic implications to protect against injury and chronic disease processes.

Animals↗

PubMed2003

Proangiogenic function of CD40 ligand-CD40 interactions.

Angiogenesis is a characteristic component of cell-mediated immune inflammation. However, little is known of the immunologic mediators of angiogenesis factor production. Interactions between CD40 ligand (CD40L) and CD40 have been shown to have pluripotent functions in inflammation, including the production of cytokines, chemokines, as well as the angiogenesis factor, vascular endothelial growth factor (VEGF), by endothelial cells. In this study we found that treatment of cultured human endothelial cells with an anti-CD40 Ab (to ligate CD40) resulted in the expression of several other angiogenesis factors, including fibroblast growth factor-2 and the receptors Flt-1 and Flt-4. To determine the proangiogenic effect of CD40L in vivo, human skin was allowed to engraft on SCID mice for 6 wk. These healed human skins express CD40 on resident endothelial cells and monocyte/macrophages, but not on CD20-expressing B cells. Skins were injected with saline, untransfected murine fibroblasts, or murine fibroblasts stably transfected with human CD40L. We found that the injection of CD40L-expressing cells, but not control cells, resulted in the in vivo expression of several angiogenesis factors (including VEGF and fibroblast growth factor) and a marked angiogenesis reaction. Mice treated with anti-VEGF failed to elicit an angiogenesis reaction in response to injection of CD40L-expressing cells, suggesting that the proangiogenic effect of CD40L in vivo is VEGF dependent. These observations imply that ligation of CD40 at a peripheral inflammatory site is of pathophysiological importance as a mediator of both angiogenesis and inflammation.

Administration, Cutaneous↗

PubMed2003

Expression patterns of vascular endothelial growth factor in human cardiac allografts: association with rejection.

BACKGROUND: Vascular endothelial growth factor (VEGF), a major angiogenesis factor, has been found to have proinflammatory properties in vivo in several chronic inflammatory diseases. However, little is known of the expression or function of VEGF in acute and chronic allograft rejection. METHODS: In a cross-sectional analysis, we evaluated the expression of VEGF by immunohistochemistry in human endomyocardial biopsies (n=101) from 10 cardiac transplant patients. We correlated expression (scores from 0-4) with CD3+ T cell, CD68+ monocyte and macrophage infiltrates, or rejection (International Society of Heart and Lung Transplantation grades 0-4). In addition, we evaluated the temporal patterns of VEGF expression in consecutive biopsies from seven patients (total of 74 biopsies) who were assessed for the development of graft vascular disease (GVD) by intravascular ultrasonography at 1 year posttransplantation. RESULTS: VEGF is expressed in normal human endomyocardial biopsies at low levels and is induced (scores >1) in association with CD3+ T cells (odds ratio [OR], 19.90; P<0.001), CD68+ monocyte and macrophage infiltrates (OR, 8.49; P<0.001), and all grades of acute rejection (OR, 5.4; P<0.001). Increases in VEGF expression were persistent during the first posttransplant year in biopsies from four patients who demonstrated evidence of GVD (mean annual score of 2.3). In contrast, limited expression of VEGF was found in three patients without GVD (mean annual score 1.2). CONCLUSIONS: These findings define VEGF as an important proinflammatory cytokine after transplantation and indicate that its expression pattern might identify patients at risk for the development of GVD.

Adult↗

PubMed2003

Proinflammatory functions of vascular endothelial growth factor in alloimmunity.

Vascular endothelial growth factor (VEGF), an established angiogenesis factor, is expressed in allografts undergoing rejection, but its function in the rejection process has not been defined. Here, we initially determined that VEGF is functional in the trafficking of human T cells into skin allografts in vivo in the humanized SCID mouse. In vitro, we found that VEGF enhanced endothelial cell expression of the chemokines monocyte chemoattractant protein 1 and IL-8, and in combination with IFN-gamma synergistically induced endothelial cell production of the potent T cell chemoattractant IFN-inducible protein-10 (IP-10). Treatment of BALB/c (H-2d) recipients of fully MHC-mismatched C57BL/6 (H-2b) donor hearts with anti-VEGF markedly inhibited T cell infiltration of allografts and acute rejection. Anti-VEGF failed to inhibit T cell activation responses in vivo, but inhibited intragraft expression of several endothelial cell adhesion molecules and chemokines, including IP-10. In addition, whereas VEGF expression was increased, neovascularization was not associated with acute rejection, and treatment of allograft recipients with the angiogenesis inhibitor endostatin failed to inhibit leukocyte infiltration of the grafts. Thus, VEGF appears to be functional in acute allograft rejection via its effects on leukocyte trafficking. Together, these observations provide mechanistic insight into the proinflammatory function of VEGF in immunity.

Animals↗