Characterization of vascular remodeling associated with pulmonary hypertension in miR-200b knockout mice
| dc.contributor.author | Seif, Samira | |
| dc.contributor.examiningcommittee | Czubryt, Michael (Physiology and Pathophysiology) Triggs-Raine, Barbara (Biochemistry and Medical Genetics) | en_US |
| dc.contributor.supervisor | Keijzer, Richard (Physiology and Pathophysiology) | en_US |
| dc.date.accessioned | 2020-01-06T17:55:44Z | |
| dc.date.available | 2020-01-06T17:55:44Z | |
| dc.date.issued | 2019-12-18 | en_US |
| dc.date.submitted | 2019-12-27T02:19:24Z | en |
| dc.degree.discipline | Physiology and Pathophysiology | en_US |
| dc.degree.level | Master of Science (M.Sc.) | en_US |
| dc.description.abstract | Abstract Introduction: Pulmonary hypertension is one of the main causes of death in congenital diaphragmatic hernia. It results from thickening of the medial and adventitial layers in the lung vessels leading to increased vessel resistance and ultimately heart failure. The underlying pathogenesis of pulmonary hypertension is poorly understood. We hypothesized that microRNA-200b (miR-200b) plays a role in vascular remodeling associated with pulmonary hypertension. To better understand the role of miR-200b we created miR-200b knockout (KO) mice and aimed to 1) evaluate the morphological pulmonary vasculature changes in miR-200b KO mice and 2) to determine the role of miR-200b in pulmonary hypertension by targeting of the vascular endothelial growth factor (VEGF) signaling pathway. Method: Verhoeff-van Gieson (VVG) staining was used to measure the medial, arterial and adventitial wall thickness of the lung vessels. VEGF-A and its receptors VEGFR-1 and VEGFR-2 expression were assessed using immunohistochemistry (IHC). Micro-computed tomography (micro-CT) was optimized and applied to demonstrate the complexity of the pulmonary vasculature at the microlevel (8 µm) with high resolution, quantitative, three -dimensional images. Results: Vascular remodeling assessment showed that miR-200b KO lungs have 35% increased arterial wall thickness, 47% medial wall thickness and 32% adventitial wall thickness in pulmonary vessels compared to normal lung (P < 0.0001). The most significant structural changes were observed in arterioles with an external diameter less than 20 or 40 µm in the miR-200b KO group. IHC results showed that VEGF-A was downregulated and VEGFR-1 was upregulated in miR-200b KO lungs. However, VEGFR-2 expression did not show any difference between miR-200b KO and WT mice. Micro-CT data did not show any difference between miR-200b KO and WT mice. Conclusion: Pulmonary hypertension in miR-200b KO mice is associated with changes in vascular morphology. Our results suggest that the absence of miR-200b results in pulmonary hypertension by vascular remodeling of the pulmonary vessels especially in arterioles. MiR-200b could also contribute to pulmonary hypertension by downregulation of VEGF-A and upregulation of VEGFR-1. | en_US |
| dc.description.note | February 2020 | en_US |
| dc.identifier.uri | http://hdl.handle.net/1993/34446 | |
| dc.language.iso | eng | en_US |
| dc.rights | open access | en_US |
| dc.subject | Congenital diaphragmatic hernia | en_US |
| dc.subject | pulmonary hypertension | en_US |
| dc.subject | miR-200b | en_US |
| dc.subject | knockout mice | en_US |
| dc.title | Characterization of vascular remodeling associated with pulmonary hypertension in miR-200b knockout mice | en_US |
| dc.type | master thesis | en_US |