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HIV and Schistosoma infections have been individually associated with pulmonary vascular disease. Co-infection with these pathogens is very common in tropical areas, with an estimate of six million people co-infected worldwide. However, the effects of HIV and Schistosoma co-exposure on the pulmonary vasculature and its impact on the development of pulmonary vascular disease are largely unknown. Here, we have approached these questions by using a non-infectious animal model based on lung embolization of Schistosoma mansoni eggs in HIV-1 transgenic (HIV) mice. Schistosome-exposed HIV mice but not wild-type (Wt) counterparts showed augmented pulmonary arterial pressure associated with markedly suppressed endothelial-dependent vasodilation, increased endothelial remodeling and vessel obliterations, formation of plexiform-like lesions and a higher degree of perivascular fibrosis. In contrast, medial wall muscularization was similarly increased in both types of mice. Moreover, HIV mice displayed an impaired immune response to parasite eggs in the lung, as suggested by decreased pulmonary leukocyte infiltration, small-sized granulomas, and augmented residual egg burden. Notably, vascular changes in co-exposed mice were associated with increased expression of proinflammatory and profibrotic cytokines, including IFN-γ and IL-17A in CD4+ and γδ T cells and IL-13 in myeloid cells. Collectively, our study shows for the first time that combined pulmonary persistence of HIV proteins and Schistosoma eggs, as it may occur in co-infected people, alters the cytokine landscape and targets the vascular endothelium for aggravated pulmonary vascular pathology. Furthermore, it provides an experimental model for the understanding of pulmonary vascular disease associated with HIV and Schistosoma co-morbidity.

Schistosomiasis is a global parasitic disease with high impact on public health in tropical areas. Schistosomiasis is a well-described cause of pulmonary arterial hypertension (PAH). The exact pathogenesis is still unclear, though inflammatory mechanisms are suspected. Another unknown is whether the changes in the pulmonary vasculature are generalized or localized. We studied 13 mice infected with cercariae for 12 weeks compared with 10 control mice. In our model, we observed that the liver was a target during infection and was enlarged more than two-fold after infection. However, right heart hypertrophy as measured by RV/(LV + S) ratio was not observed at this time point. Moreover, we noticed that 72% of the sampled lobes (92% of the lungs) harvested from these animals costained evidence of granulomatous changes, secondary to egg deposition. We systemically mapped the distribution of granulomatous lesions in right lung lobes (n = 43) of infected mice. We observed that the distribution of the granulomatous lesions was heterogeneous. Remodeled pulmonary vessels were seen in 26% of the lobes (46% of the lungs) and were observed only in close proximity to the granuloma. No remodeling was observed in the absence of granulomas. These findings support the view that pulmonary vascular remodeling is caused by the local presence of granulomas in PAH associated with schistosomiasis. The heterogeneous nature of the remodeling partly explains why many patients with schistosomiasis do not develop pulmonary hypertension.

Pulmonary hypertension (PH) is characterized by increased proliferation and apoptosis resistance of pulmonary artery smooth muscle cells (PASMCs). Forkhead box O (FoxO) transcription factors are key regulators of cellular proliferation. Here we show that in pulmonary vessels and PASMCs of human and experimental PH lungs, FoxO1 expression is downregulated and FoxO1 is inactivated via phosphorylation and nuclear exclusion. These findings could be reproduced using ex vivo exposure of PASMCs to growth factors and inflammatory cytokines. Pharmacological inhibition and genetic ablation of FoxO1 in smooth muscle cells reproduced PH features in vitro and in vivo. Either pharmacological reconstitution of FoxO1 activity using intravenous or inhaled paclitaxel, or reconstitution of the transcriptional activity of FoxO1 by gene therapy, restored the physiologically quiescent PASMC phenotype in vitro, linked to changes in cell cycle control and bone morphogenic protein receptor type 2 (BMPR2) signaling, and reversed vascular remodeling and right-heart hypertrophy in vivo. Thus, PASMC FoxO1 is a critical integrator of multiple signaling pathways driving PH, and reconstitution of FoxO1 activity offers a potential therapeutic option for PH., PH is a severe and debilitating disease characterized by remodeling of the pulmonary vessels, leading to a progressive increase in pulmonary vascular resistance, increased afterload on the right ventricle (RV) [...]

Regional alveolar hypoxia causes local vasoconstriction in the lung, shifting blood flow from hypoxic to normoxic areas, thereby maintaining gas exchange. This mechanism is known as hypoxic pulmonary vasoconstriction (HPV). Disturbances in HPV can cause life-threatening hypoxemia whereas chronic hypoxia triggers lung vascular remodeling and pulmonary hypertension. The signaling cascade of this vitally important mechanism is still unresolved. Using transient receptor potential channel 6 (TRPC6)-deficient mice, we show that this channel is a key regulator of acute HPV as this regulatory mechanism was absent in [TRPC6.sup.-/-] mice whereas the pulmonary vasoconstrictor response to the thromboxane mimetic U46619 was unchanged. Accordingly, induction of regional hypoventilation resulted in severe arterial hypoxemia in [TRPC6.sup.-/-] but not in WT mice. This effect was mirrored by a lack of hypoxiainduced cation influx and currents in smooth-muscle cells from precapillary pulmonary arteries (PASMC) of [TRPC6.sup.-/-] mice. In both WT and [TRPC6.sup.-/-] PASMC hypoxia caused diacylglycerol (DAG) accumulation. DAG seems to exert its action via TRPC6, as DAG kinase inhibition provoked a cation influx only in WT but not in [TRPC6.sup.-/-] PASMC. Notably, chronic hypoxia-induced pulmonary hypertension was independent of TRPC6 activity. We conclude that TRPC6 plays a unique and indispensable role in acute hypoxic pulmonary vasoconstriction. Manipulation of TRPC6 function may thus offer a therapeutic strategy for the control of pulmonary hemodynamics and gas exchange. hypoxia-induced diacylglycerol accumulation | precapillary pulmonary arterial smooth-muscle cells | pulmonary hypertension | transient receptor potential channel 6-deficient mouse model | arterial hypoxemia