The angiopietin-1–Tie2 pathway prevents rather than promotes pulmonary arterial hypertension in transgenic mice

The role of the angiopoietin-1 (Ang1)–Tie2 pathway in the pathogenesis of pulmonary arterial hypertension (PAH) is controversial. Although Ang1 is well known to prevent endothelial activation and injury in systemic vascular beds, this pathway has been suggested to mediate pulmonary vascular remodeling in PAH. Therefore, we used transgenic models to determine the effect of increased or decreased Tie2 activity on the development of PAH. We now report modest spontaneous elevation in right ventricular systolic pressure in Tie2-deficient mice (Tie2+/−) compared with wild-type (WT) littermate controls, which was exacerbated upon chronic exposure to the clinically relevant PAH triggers, serotonin (5-HT) or interleukin-6 (IL-6). Moreover, overexpression of Ang1 in transgenic mice had no deleterious effect on pulmonary hemodynamics and, if anything, blunted the response to 5-HT. Exposure to 5-HT or IL-6 also decreased lung Ang1 expression, further reducing Tie2 activity and inducing pulmonary apoptosis in the Tie2+/− group only. Similarly, cultured pulmonary artery endothelial cells subjected to Tie2 silencing demonstrated increased susceptibility to apoptosis after 5-HT treatment. Finally, treatment of Tie2-deficient mice with Z-VAD, a pan-caspase inhibitor, prevented the pulmonary hypertensive response to 5-HT. Thus, these findings firmly establish that endothelial survival signaling via the Ang1–Tie2 pathway is protective in PAH

Prevention of LPS-Induced Acute Lung Injury in Mice by Mesenchymal Stem Cells Overexpressing Angiopoietin 1

Using a mouse model of acute respiratory distress syndrome, Duncan Stewart and colleagues report that rescue with mesenchymal stem cells expressing human angiopoietin 1 can avert lung injury from lipopolysaccharide

Is "greenness" priced in the market? Evidence from green bond issuance in China

Green bonds are bonds with a defined use of proceeds toward mitigating and adapting to climate change and solving environmental problems. Although the green bond market has expanded rapidly in recent years and has attracted great investment attention, whether investors can identify greenwashing behaviors remains a primary concern. This article takes advantage of the unique feature of the Chinese green bond market that allows a proportion of the proceeds to be used for nongreen purposes. The authors find that greener bonds (more proceeds are used for green projects) are sold at a premium. This pricing differential is primarily driven by bonds with proceeds used 100% for green projects. The authors also show that green bonds verified by a third party have lower yield spreads and the effect is stronger for more reputable third parties. Overall, the results suggest that investors reward only fully green bonds and that investors can discern "greenwashing.

Numerical Investigation of Flow around Two Tandem Identical Trapezoidal Cylinders

The trapezoidal beam structure is ubiquitous in giant engineering equipment, while their aerodynamic characteristics have not been clearly understood. Numerical simulation method was adopted to investigate the flow around two tandem identical trapezoidal cylinders. The study was conducted using a Reynolds number of 2.2 × 104, and with a spacing ratio varying from 0.5 to 10. The incompressible two-dimensional finite volume method was used for solving Reynolds-Averaged Navier–Stokes (RANS) equations with realizable k−ε model. The effects of cylinder geometry and spacing between the cylinders on aerodynamic characteristics, unsteady flow patterns, time-averaged flow characteristics, and flow instability was studied. The results show that the flow around the two tandem trapezoidal cylinders is highly dependent on the spacing ratio. The flow modes can be classified into: extended-body regime (Mode I, S∗ ≤ 1), reattachment regime (Mode II, 2 ≤ S∗ ≤ 3), and binary regime (Mode III, S∗ ≥ 4). We explored their respective flow characteristics and distinctions through the force/pressure coefficients, time-average streamwise velocity, and the flow field evolution

Targeting extracellular vesicle delivery to the lungs by microgel encapsulation

Abstract Extracellular vesicles (EVs) secreted by stem and progenitor cells have significant potential as cell‐free ‘cellular’ therapeutics. Yet, small EVs (<200 nm) are rapidly cleared after systemic administration, mainly by the liver, presenting challenges targeting EVs to a specific organ or tissue. Microencapsulation using natural nano‐porous hydrogels (microgels) has been shown to enhance engraftment and increase the survival of transplanted cells. We sought to encapsulate EVs within microgels to target their delivery to the lung by virtue of their size‐based retention within the pulmonary microcirculation. Mesenchymal stromal cell (MSC) derived EVs were labelled with the lipophilic dye (DiR) and encapsulated within agarose‐gelatin microgels. Endothelial cells and bone marrow derived macrophages were able to take up EVs encapsulated in microgels in vitro, but less efficiently than the uptake of free EVs. Following intrajugular administration, microgel encapsulated EVs were selectively retained within the lungs for 72h, while free EVs were rapidly cleared by the liver. Furthermore, microgel‐loaded EVs demonstrated greater uptake by lung cells, in particular CD45+ immune cells, as assessed by flow cytometry compared to free EVs. Microencapsulation of EVs may be a novel tool for enhancing the targeted delivery of EVs for future therapeutic applications

Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions

Familial pulmonary arterial hypertension (PAH) is associated with mutations in bone morphogenetic protein type II receptor (BMPR2). Many of these mutations occur in the BMPR2 tail domain, leaving the SMAD functions intact. To determine the in vivo consequences of BMPR2 tail domain mutation, we created a smooth muscle-specific doxycycline-inducible BMPR2 mutation with an arginine to termination mutation at amino acid 899. When these SM22-rtTA x TetO7-BMPR2R899X mice had transgene induced for 9 wk, starting at 4 wk of age, they universally developed pulmonary vascular pruning as assessed by fluorescent microangiography. Approximately one-third of the time, the induced animals developed elevated right ventricular systolic pressures (RVSP), associated with extensive pruning, muscularization of small pulmonary vessels, and development of large structural pulmonary vascular changes. These lesions included large numbers of macrophages and T cells in their adventitial compartment as well as CD133-positive cells in the lumen. Small vessels filled with CD45-positive and sometimes CD3-positive cells were a common feature in all SM22-rtTA x TetO7-BMPR2R899X mice. Gene array experiments show changes in stress response, muscle organization and function, proliferation, and apoptosis and developmental pathways before RVSP increases. Our results show that the primary phenotypic result of BMPR2 tail domain mutation in smooth muscle is pulmonary vascular pruning leading to elevated RVSP, associated with early dysregulation in multiple pathways with clear relevance to PAH. This model should be useful to the research community in examining early molecular and physical events in the development of PAH and as a platform to validate potential treatments