Wnt5a attenuates hypoxia-induced pulmonary arteriolar remodeling and right ventricular hypertrophy in mice

Jin, Yuling; Wang, Wang; Chai, Shude; Liu, Jie; Yang, Ting; Wang, Jun

doi:10.1177/1535370215584889

Cited by 18 publications

(16 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Wingless (Wnt) signaling pathway is divided into canonical signaling pathway and non-canonical signaling pathway. As a member of Wnt family, mounting evidence indicated that wnt5a involved in the pathogenesis of PH [13,14,23,24], wnt5a was reported to have the role of regulating human endothelial cell proliferation and migration via noncanonical signaling [25] and inhibiting hypoxia-induced PASMC proliferation via suppression of of β1-catenin/cyclin D1 [26].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling

Zhang

Liu

et al. 2020

Respir Res

View full text Add to dashboard Cite

Background: Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling, right ventricular hypertrophy and failure. So far no effective treatment exists for this disease; hence, novel approaches are urgently needed. The aim of the present research was to observe the treatment effect of mesenchymal stromal cell derived exosomes and reveal the mechanism. Methods: Monocrotaline (MCT)-induced PH in rats and hypoxia-induced cell damage model were established, respectively. Exosomes derived from the supernatant of human umbilical cord mesenchymal stem cells (MSC-exo) were injected into MCT-PH model rat or added into the cells cultured medium. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot methods were used in vivo and vitro. Results: The results showed that MSC-exo could significantly attenuate right ventricular (RV) hypertrophy and pulmonary vascular remodelling in MCT-PH rats. In the cell culture experiments, we found that MSC-exo could significantly inhibit hypoxia-induced pulmonary arterial endothelial cell (PAEC) apoptosis and pulmonary arterial smooth muscle cells (PASMC) proliferation. Furthermore, the pulmonary arterioles endothelial-to-mesenchymal transition (EndMT) was obviously suppressed. Moreover, the present study suggest that MSC-exo can significantly upregulate the expression of Wnt5a in MCT-PH rats and hypoxic pulmonary vascular cells. Furthermore, with Wnt5a gene silencing, the therapeutic effect of MSC-exo against hypoxia injury was restrained. Conclusions: Synthetically, our data provide a strong evidence for the therapeutic of MSC-exo on PH, more importantly, we confirmed that the mechanism was associated with up-regulation of the expression of Wnt5a. These results offer a theoretical basis for clinical prevention and treatment of PH.

show abstract

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling

Zhang

Liu

et al. 2020

Respir Res

View full text Add to dashboard Cite

show abstract

“…The measurements were performed as previously described [ 16 , 17 ]. Following anaesthesia of the mice with 2% sodium pentobarbital (50 mg/kg i.p.…”

Section: Methodsmentioning

confidence: 99%

IL-33 Initiates Vascular Remodelling in Hypoxic Pulmonary Hypertension by up-Regulating HIF-1α and VEGF Expression in Vascular Endothelial Cells

Liu¹,

Wang²,

Wang³

et al. 2018

EBioMedicine

Self Cite

138

View full text Add to dashboard Cite

IL-33 may play a role in the vascular remodelling of hypoxic pulmonary hypertension (PH) but the precise mechanisms are still unclear. We hypothesized that hypoxia promotes expression of IL-33 and its receptor ST2 on vascular endothelial cells, which in turn leads to dysfunction of vascular endothelial cells and smooth muscle cells contributing to PH. Immunohistochemistry showed that immunoreactivity for IL-33 and ST2 was significantly increased in lung tissue of murine model of hypoxia-induced PH (HPH) and of subjects with bronchiectasis-PH. trans-Thoracic echocardiography showed that haemodynamic changes and right ventricular hypertrophy associated with HPH were significantly abrogated in St2−/− compared with WT mice. Administration of IL-33 further exacerbated these changes in the hypoxia-exposed WT mice. In vitro, hypoxia significantly increased IL-33/ST2 expression by human pulmonary arterial endothelial cells (HPAECs), while exogenous IL-33 enhanced proliferation, adhesiveness and spontaneous angiogenesis of HPAECs. Knockdown of endogenous Il33 or St2 using siRNA transfection significantly suppressed these effects in both normoxic and hypoxic culture-conditions. Deletion of the St2 gene attenuated hypoxia-induced, elevated lung expression of HIF-1α/VEGFA/VEGFR-2/ICAM-1, while administration of exogenous VEGFA partially reversed the attenuation of the haemodynamic indices of PH. Correspondingly, knockdown of the St2 or Hif1α genes almost completely abrogated IL-33-induced expression of HIF-1α/VEGFA/VEGFR-2 by HPAECs in vitro. Further, IL-33-induced angiogenesis by HPAECs was extensively abrogated by knockdown of the Hif1α/Vegfa or Vegfr2 genes. These data suggest that hypoxia induces elevated expression of IL-33/ST2 by HPAECs which, at least partly by increasing downstream expression of HIF-1α and VEGF initiates vascular remodelling resulting in HPH.

show abstract

“…Pulmonary artery resistance vessels from patients with idiopathic PAH demonstrated endothelial upregulation of β-catenin in idiopathic PAH vessels that correlated with upregulation of RhoA, ROCK, and Rac1 as assessed by immunohistochemistry and qPCR ( Laumanns et al, 2009 ). Finally, downregulation of β-catenin reduces hypoxia-induced PASMC proliferation and PA remodeling in hypoxia models of PH ( Yu et al, 2013 ; Alapati et al, 2014 ; Jin et al, 2015 ). These data together indicate a potential role for β-catenin activation downstream of stiffness-induced vascular remodeling in PH.…”

Section: Key Molecular Pathways Involved In Mechanobiological Feedbacmentioning

confidence: 98%

Mechanobiological Feedback in Pulmonary Vascular Disease

et al. 2018

View full text Add to dashboard Cite

Vascular stiffening in the pulmonary arterial bed is increasingly recognized as an early disease marker and contributor to right ventricular workload in pulmonary hypertension. Changes in pulmonary artery stiffness throughout the pulmonary vascular tree lead to physiologic alterations in pressure and flow characteristics that may contribute to disease progression. These findings have led to a greater focus on the potential contributions of extracellular matrix remodeling and mechanical signaling to pulmonary hypertension pathogenesis. Several recent studies have demonstrated that the cellular response to vascular stiffness includes upregulation of signaling pathways that precipitate further vascular remodeling, a process known as mechanobiological feedback. The extracellular matrix modifiers, mechanosensors, and mechanotransducers responsible for this process have become increasingly well-recognized. In this review, we discuss the impact of vascular stiffening on pulmonary hypertension morbidity and mortality, evidence in favor of mechanobiological feedback in pulmonary hypertension pathogenesis, and the major contributors to mechanical signaling in the pulmonary vasculature.

show abstract

Wnt5a attenuates hypoxia-induced pulmonary arteriolar remodeling and right ventricular hypertrophy in mice

Cited by 18 publications

References 53 publications

Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling

Mesenchymal stromal cell-derived exosomes improve pulmonary hypertension through inhibition of pulmonary vascular remodeling

IL-33 Initiates Vascular Remodelling in Hypoxic Pulmonary Hypertension by up-Regulating HIF-1α and VEGF Expression in Vascular Endothelial Cells

Mechanobiological Feedback in Pulmonary Vascular Disease

Contact Info

Product

Resources

About