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Articles by S Yla Herttuala
Total Records ( 4 ) for S Yla Herttuala
  A. I Nykanen , H Sandelin , R Krebs , M. A. I Keranen , R Tuuminen , T Karpanen , Y Wu , B Pytowski , P. K Koskinen , S Yla Herttuala , K Alitalo and K. B. Lemstrom
 

Background— Lymphatic network and chemokine-mediated signals are essential for leukocyte traffic during the proximal steps of alloimmune response. We aimed to determine the role of lymphatic vessels and their principal growth signaling pathway, vascular endothelial growth factor (VEGF)-C/D/VEGFR-3, during acute and chronic rejection in cardiac allografts.

Methods and Results— Analysis of heterotopically transplanted rat cardiac allografts showed that chronic rejection increased VEGF-C+ inflammatory cell and hyaluronan receptor-1 (LYVE-1)+ lymphatic vessel density. Allograft lymphatic vessels were VEGFR-3+, contained antigen-presenting cells, and produced dendritic cell chemokine CCL21. Experiments with VEGFR-3/LacZ mice or mice with green fluorescent protein–positive bone marrow cells as cardiac allograft recipients showed that allograft lymphatic vessels originated almost exclusively from donor cells. Intraportal adenoviral VEGFR-3-Ig (Ad.VEGFR-3-Ig/VEGF-C/D-Trap) perfusion was used to inhibit VEGF-C/D/VEGFR-3 signaling. Recipient treatment with Ad.VEGFR-3-Ig prolonged rat cardiac allograft survival. Ad.VEGFR-3-Ig did not affect allograft lymphangiogenesis but was linked to reduced CCL21 production and CD8+ effector cell entry in the allograft. Concomitantly, Ad.VEGFR-3-Ig reduced OX62+ dendritic cell recruitment and increased transcription factor Foxp3 expression in the spleen. In separate experiments, treatment with a neutralizing monoclonal VEGFR-3 antibody reduced arteriosclerosis, the number of activated lymphatic vessels expressing VEGFR-3 and CCL21, and graft-infiltrating CD4+ T cells in chronically rejecting mouse cardiac allografts.

Conclusions— These results show that VEGFR-3 participates in immune cell traffic from peripheral tissues to secondary lymphoid organs by regulating allograft lymphatic vessel CCL21 production and suggest VEGFR-3 inhibition as a novel lymphatic vessel–targeted immunomodulatory therapy for cardiac allograft rejection and arteriosclerosis.

  A Anisimov , A Alitalo , P Korpisalo , J Soronen , S Kaijalainen , V. M Leppanen , M Jeltsch , S Yla Herttuala and K. Alitalo
 

The therapeutic potential of vascular endothelial growth factor (VEGF)-C and VEGF-D in skeletal muscle has been of considerable interest as these factors have both angiogenic and lymphangiogenic activities. Previous studies have mainly used adenoviral gene delivery for short-term expression of VEGF-C and VEGF-D in pig, rabbit, and mouse skeletal muscles. Here we have used the activated mature forms of VEGF-C and VEGF-D expressed via recombinant adeno-associated virus (rAAV), which provides stable, long-lasting transgene expression in various tissues including skeletal muscle. Mouse tibialis anterior muscle was transduced with rAAV encoding human or mouse VEGF-C or VEGF-D. Two weeks later, immunohistochemical analysis showed increased numbers of both blood and lymph vessels, and Doppler ultrasound analysis indicated increased blood vessel perfusion. The lymphatic vessels further increased at the 4-week time point were functional, as shown by FITC-lectin uptake and transport. Furthermore, receptor activation and arteriogenic activity were increased by an alanine substitution mutant of human VEGF-C (C137A) having an increased dimer stability and by a chimeric CAC growth factor that contained the VEGF receptor-binding domain flanked by VEGF-C propeptides, but only the latter promoted significantly more blood vessel perfusion when compared to the other growth factors studied. We conclude that long-term expression of VEGF-C and VEGF-D in skeletal muscle results in the generation of new functional blood and lymphatic vessels. The therapeutic value of intramuscular lymph vessels in draining tissue edema and lymphedema can now be evaluated using this model system.

  I Laitinen , A Saraste , E Weidl , T Poethko , A. W Weber , S. G Nekolla , P Leppanen , S Yla Herttuala , G Holzlwimmer , A Walch , I Esposito , H. J Wester , J Knuuti and M. Schwaiger
 

Background— 18F-Galacto-RGD is a positron emission tomography (PET) tracer binding to vβ3 integrin that is expressed by macrophages and endothelial cells in atherosclerotic lesions. Therefore, we evaluated 18F-galacto-RGD for imaging vascular inflammation by studying its uptake into atherosclerotic lesions of hypercholesterolemic mice in comparison to deoxyglucose.

Methods and results— Hypercholesterolemic LDLR–/–ApoB100/100 mice on a Western diet and normally fed adult C57BL/6 control mice were injected with 18F-galacto-RGD and 3H-deoxyglucose followed by imaging with a small animal PET/CT scanner. The aorta was dissected 2 hours after tracer injection for biodistribution studies, autoradiography, and histology. Biodistribution of 18F-galacto-RGD was higher in the atherosclerotic than in the normal aorta. Autoradiography demonstrated focal 18F-galacto-RGD uptake in the atherosclerotic plaques when compared with the adjacent normal vessel wall or adventitia. Plaque-to-normal vessel wall ratios were comparable to those of deoxyglucose. Although angiogenesis was not detected, 18F-galacto-RGD uptake was associated with macrophage density and deoxyglucose accumulation in the plaques. Binding to atherosclerotic lesions was efficiently blocked in competition experiments. In vivo imaging visualized 18F-galacto-RGD uptake colocalizing with calcified lesions of the aortic arch as seen in CT angiography.

Conclusions— 18F-Galacto-RGD demonstrates specific uptake in atherosclerotic lesions of mouse aorta. In this model, its uptake was associated with macrophage density. 18F-Galacto-RGD is a potential tracer for noninvasive imaging of inflammation in atherosclerotic lesions.

 
 
 
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