| 1. |
- Chang, Ya-Ting, et al.
(författare)
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Perlecan heparan sulfate deficiency impairs pulmonary vascular development and attenuates hypoxic pulmonary hypertension
- 2015
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Ingår i: Cardiovascular Research. - : Oxford University Press (OUP). - 0008-6363 .- 1755-3245. ; 107:1, s. 20-31
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Tidskriftsartikel (refereegranskat)abstract
- Aims Excessive vascular cell proliferation is an important component of pulmonary hypertension (PH). Perlecan is the major heparan sulfate (HS) proteoglycan in the vascular extracellular matrix. It binds growth factors, including FGF2, and either restricts or promotes cell proliferation. In this study, we have explored the effects of perlecan HS deficiency on pulmonary vascular development and in hypoxia-induced PH. Methods and results In normoxia, Hspg2(Delta 3/Delta 3) mice, deficient in perlecan HS, had reduced pericytes and muscularization of intra-acinar vessels. Pulmonary angiography revealed a peripheral perfusion defect. Despite these abnormalities, right ventricular systolic pressure (RVSP) and myocardial mass remained normal. After 4 weeks of hypoxia, increases in the proportion of muscularized vessels, RVSP, and right ventricular hypertrophy were significantly less in Hspg2(Delta 3/Delta 3) compared with wild type. The early phase of hypoxia induced a significantly lower increase in fibroblast growth factor receptor-1 (FGFR1) protein level and receptor phosphorylation, and reduced pulmonary artery smooth muscle cell (PASMC) proliferation in Hspg2(Delta 3/Delta 3). At 4 weeks, FGF2 mRNA and protein were also significantly reduced in Hspg2(Delta 3/Delta 3) lungs. Ligand and carbohydrate engagement assay showed that perlecan HS is required for HS-FGF2-FGFR1 ternary complex formation. In vitro, proliferation assays showed that PASMC proliferation is reduced by selective FGFR1 inhibition. PASMC adhesion to fibronectin was higher in Hspg2(Delta 3/Delta 3) compared with wild type. Conclusions Perlecan HS chains are important for normal vascular arborization and recruitment of pericytes to pulmonary vessels. Perlecan HS deficiency also attenuates hypoxia-induced PH, where the underlying mechanisms involve impaired FGF2/FGFR1 interaction, inhibition of PASMC growth, and altered cell-matrix interactions.
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| 2. |
- Tseng, Chi-Nan
(författare)
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Interactions between leukocytes, platelets and the endothelium in vein graft failure
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Autologous venous grafts are preferred conduits in bypass surgery due to their length, easy harvesting, and feasibility. However, development of intimal hyperplasia decreases long-term patency rate in venous grafts prompting close clinical surveillance and further intervention. Mechanical forces, inflammation, and shear stress responses in venous grafts after surgical transfer may be involved in the development of intimal hyperplasia. This thesis focuses on inflammatory reactions in venous grafts. We hypothesized that interactions between leukocytes, platelets and endothelial cells induce intimal hyperplasia resulting in venous graft failure. We demonstrate that VGs obtained by end-to-end anastomosis of the inferior vena cava (IVC) from donor mice grafted to the abdominal aorta in recipients suffer extensive endothelial injury, platelet deposition and leukocyte invasion early after grafting. Re-endothelialization of interposed venous grafts was completed after 4 weeks. Regenerated endothelium displayed normal resistance to recruitment of leukocytes. Thus, we found that there is a time window during the first weeks following grafting in which venous grafts are susceptible to vessel injury and inflammation. Leukocyte recruitment on inflammatory endothelium initiates with margination, capture followed by rolling, firm adhesion and transmigration. We hypothesized that absence or functionblockage of leukocyte adhesion molecules P-selectin and E-selectin that are important for rolling may influence development of intimal hyperplasia in venous grafts by reduction of the recruitment of leukocytes. Indeed, intimal hyperplasia was significantly reduced in E- and P-selectin double deficient mice compared to WT both at 28 days and 63 days after VG transfer. This was paralleled by a reduction in the recruitment of leukocytes to the graft wall. Similar findings were made in WT mice treated with a combination of function-blocking antibodies against P- and E-selectin. The effect of P-selectin alone was addressed using P-selectin deficient mice. We found that intimal hyperplasia was significantly attenuated in mice deficient in P-selectin compared to WT mice 28 days after surgery concomitant with decreased leukocyte invasion. Interestingly, single-dose blockage of P-selectin or its leukocytic ligand PSGL-1 at the time of surgery could block the function of these molecules for up to 10 days and reduced later formation of intimal hyperplasia. Hence, early inhibition of these molecules has potential therapeutic effects on long-term vein graft failure. Platelets strongly influence haemostasis, inflammation and tissue regeneration after vascular injury, which are all represented in the period of re-endothelialization after venous graft transfer. We tested whether absence or function-blockage of platelets could influence intimal hyperplasia in venous grafts. We first used antiserum depletion of platelets for 12 days following surgical grafting. Indeed, IH and leukocyte invasion were reduced in platelet-depleted mice. Moreover, inhibition of integrin αIIbβ3, the main aggregation receptor on platelets, also reduced IH and leukocyte recruitment in the graft wall. The reduction of intimal hyperplasia in mice treated with the antibody against integrin αIIbβ3 was paralleled by radical reductions of the number of adherent platelets and leukocytes on the luminal surface of grafts one hour following grafting. In summary, our work emphasizes the role of interactions between leukocytes, platelets and the vessel wall in venous grafts during their adaptation to the arterial circulation. These mechanisms constitute attractive targets for the development of further preventive pharmacological strategies against vein graft failure.
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| 3. |
- Zhu, Nan, et al.
(författare)
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Sandwiched confinement of quantum dots in graphene matrix for efficient electron transfer and photocurrent production.
- 2015
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Quantum dots (QDs) and graphene are both promising materials for the development of new-generation optoelectronic devices. Towards this end, synergic assembly of these two building blocks is a key step but remains a challenge. Here, we show a one-step strategy for organizing QDs in a graphene matrix via interfacial self-assembly, leading to the formation of sandwiched hybrid QD-graphene nanofilms. We have explored structural features, electron transfer kinetics and photocurrent generation capacity of such hybrid nanofilms using a wide variety of advanced techniques. Graphene nanosheets interlink QDs and significantly improve electronic coupling, resulting in fast electron transfer from photoexcited QDs to graphene with a rate constant of 1.3 × 10(9) s(-1). Efficient electron transfer dramatically enhances photocurrent generation in a liquid-junction QD-sensitized solar cell where the hybrid nanofilm acts as a photoanode. We thereby demonstrate a cost-effective method to construct large-area QD-graphene hybrid nanofilms with straightforward scale-up potential for optoelectronic applications.
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