Investigating the impact of endothelial BMPR2 loss on the proliferative response to bone morphogenetic protein 9 in pulmonary arterial hypertension

dc.contributor.authorTheilmann, Anneen
dc.contributor.departmentBiomedical and Molecular Sciencesen
dc.contributor.supervisorOrmiston, Marken
dc.date.accessioned2019-07-23T16:05:05Z
dc.date.available2019-07-23T16:05:05Z
dc.degree.grantorQueen's University at Kingstonen
dc.description.abstractObjective: Pulmonary arterial hypertension (PAH) is a disease of proliferative vascular occlusion that is strongly linked to heterozygous mutations in BMPR2, the gene encoding the bone morphogenetic protein (BMP) type II receptor (BMPR-II). The endothelial-selective BMPR-II ligand, BMP9, has been shown to reverse disease in animal models of PAH and suppress the proliferation of healthy endothelial cells. However, the impact of BMPR2 loss on the antiproliferative actions of BMP9 has yet to be assessed in endothelial cells from PAH patients. Approach: BMP9 responses were assessed in blood outgrowth endothelial cells (BOECs) from PAH patients and controls, as well as human pulmonary artery endothelial cells (HPAECs) with or without BMPR2 silencing. Mouse pulmonary endothelial cells (MPECs), bearing a wildtype genome or a heterozygous or homozygous deletion of Bmpr2, were isolated from endothelial-conditional knockout mice (Bmpr2EC+/+, Bmpr2EC+/- or Bmpr2EC-/-). These mice were also assessed in vivo for altered retinal and lung angiogenesis following post-natal BMP9 administration. Results: BMP9 suppressed proliferation in control endothelial cells, but increased proliferation in PAH patient BOECs, BMPR2 silenced HPAECs and Bmpr2-/- MPECs. This proliferative shift was not linked to altered metabolic activity or interactions with canonical TGFβ signaling, but was associated with the prolonged induction of the canonical BMP targets, the inhibitor of DNA-binding/differentiation genes, ID1 and ID2. In vivo, BMP9 administration reduced neonatal retinal and pulmonary vascular density in controls, but enhanced both measures in Bmpr2EC-/- mice. Conclusion: Loss of BMPR2 results in a shift of the endothelial BMP9 response towards enhanced proliferation. This finding has potential implications for the clinical translation of BMP9 for the treatment of PAH.en
dc.description.degreeM.Sc.en
dc.embargo.liftdate2024-07-22T18:52:49Z
dc.embargo.termsI am restricting this thesis as the data have not yet been published.en
dc.identifier.urihttp://hdl.handle.net/1974/26410
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectPulmonary Hypertensionen
dc.subjectEndothelialen
dc.subjectBone Morphogenetic Proteinen
dc.subjectProliferationen
dc.subjectCell Signalingen
dc.subjectBone Morphogenetic Protein Receptor Type IIen
dc.titleInvestigating the impact of endothelial BMPR2 loss on the proliferative response to bone morphogenetic protein 9 in pulmonary arterial hypertensionen
dc.typethesisen
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