Effect of vascular endothelial growth factor and its receptor KDR on the transendothelial migration and local trafficking of human T cells in vitro and in vivo.

In these studies, we find that the vascular endothelial growth factor (VEGF) receptor KDR is expressed on subsets of mitogen-activated CD4(+) and CD8(+) T cells in vitro. We also found that KDR colocalizes with CD3 on mitogen-activated T cells in vitro and on infiltrates within rejecting human allografts in vivo. To evaluate whether VEGF and KDR mediate lymphocyte migration across endothelial cells (ECs), we used an in vitro live-time transmigration model and observed that both anti-VEGF and anti-KDR antibodies inhibit the transmigration of both CD4(+) and CD8(+) T cells across tumor necrosis factor α (TNFα)-activated, but not unactivated ECs. In addition, we found that interactions among CD4(+) or CD8(+) T cells and TNFα-activated ECs result in the induction of KDR on each T cell subset, and that KDR-expressing lymphocytes preferentially transmigrate across TNFα-activated ECs. Finally, using a humanized severe combined immunodeficient mouse model of lymphocyte trafficking, we found that KDR-expressing lymphocytes migrate into human skin in vivo, and that migration is reduced in mice treated with a blocking anti-VEGF antibody. These observations demonstrate that induced expression of KDR on subsets of T cells, and locally expressed VEGF, facilitate EC-dependent lymphocyte chemotaxis, and thus, the localization of T cells at sites of inflammation.

Thyroid hormone-induced cardiac mechano growth factor expression depends on beating activity.

The mechano growth factor (MGF), a splice variant of the IGF-I gene, was first discovered in mechanically overloaded skeletal muscle and was shown to play an important role in proliferation of muscle stem cells. Since then, the presence and effects of MGF have been demonstrated in other tissues. MGF has been shown to act neuroprotectively during brain ischemia, and pretreatment with MGF before myocardial infarction improves cardiac function. Because MGF plays a permissive role in exercise-induced skeletal muscle hypertrophy, we hypothesize that MGF is commonly involved in cardiac hypertrophy. To investigate the regulation of MGF expression in heart, mice were treated with thyroid hormone (T(3)) for 12 d to induce physiological cardiac hypertrophy. MGF mRNA expression was specifically increased in midregions of the septum and left ventricular wall. Interestingly, MGF expression strongly correlated with the increased or decreased beating frequency of hyperthyroid and hypothyroid hearts. To further investigate the mechanically dependent induction of MGF, neonatal rat cardiomyocytes were isolated and exposed to T(3). Upon T(3) treatment, cardiomyocytes increased both contractile activity measured as beats per minute and MGF as well as IGF-IEa mRNA expression. Importantly, when cardiomyocytes were contractile arrested by KCl, simultaneous exposure to T(3) prevented the up-regulation of MGF, whereas IGF-IEa was still induced. These studies demonstrated that MGF but not IGF-IEa expression is dependent on beating activity. These findings suggest that MGF is specifically stimulated by mechanical loading of the heart to mediate the hypertrophic response to thyroid hormone.

The role of nitric oxide in renal transplantation.

This review discusses the concept that nitric oxide synthase (NOS) may orchestrate both the inflammatory response to the renal allograft and anti-inflammatory defense in the graft itself. NO is produced by endothelial, epithelial, as well as inflammatory cells. In the setting of transplantation, the endothelium is the first lining to be subjected to the early response to injury. In turn, activated endothelial cells facilitate leukocyte recruitment, immune-mediated injury, and angiogenesis. On activation by inflammatory stimuli, endothelial cells up-regulate multiple vasoactive substances, oxygen radicals, cytokines, chemokines, and growth factors. Therefore, endothelial integrity, especially the expression of protecting vasoactive agents, such as NO, may be a key factor in resistance or sensitivity to transplantation-mediated injury. Thus, evaluating the mechanisms by which NO is involved in either protecting or injuring the transplanted allogeneic kidney is important for our understanding of renal allograft rejection. This review focuses on the role of NO in the inflammatory endothelial-leukocyte interactions, which are implicated in acute and chronic rejection of the transplanted kidney.

L-arginine supplementation improves function and reduces inflammation in renal allografts.

Recovery from ischemia/reperfusion and immune-mediated injury in the renal transplant is associated with reduced renal hemodynamics and increased leukocyte infiltration. In diverse models of renal failure, L-arginine supplementation improved hemodynamics and reduced inflammation. However in a proinflammatory environment, L-arginine can worsen renal injury. This study investigated the therapeutic potential of L-arginine supplementation in allogeneic renal transplantation: Brown Norway rat kidneys were transplanted into Lewis rat recipients, with one native kidney remaining. Recipients received low-dose cyclosporin A (2.5 mg/kg per d subcutaneously) to obtain moderate vascular and interstitial rejection, with or without 1% L-arginine in drinking water for 7 d posttransplantation. Transplantation increased renal vasoconstriction (from 16.9 +/- 1.33 to 35.1 +/- 8.6 units; P: < 0.01), thereby reducing GFR (from 0.96 +/- 0.09 to 0.48 +/- 0.10 ml/min; P: < 0.05). Treatment with L-arginine restored renal graft function to levels found in normal donors (renal vascular resistance, 15.7 +/- 1.69 units; GFR, 0.80 +/- 0.06 ml/min). L-arginine significantly reduced vascular occlusion because of less inflammation, endothelial disruption, and thrombosis. L-arginine also decreased tubulitis, interstitial injury, and macrophage infiltration. These protective effects suggest that L-arginine might be useful as additive therapy to conventional immune suppression.