Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486283
Title: The Protective Role of Bone Morphogenetic Proteins in Pulmonary Artery
Author: Din, Sarah
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2008
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Abstract:
Familial primary pulmonary arterial hypertension (FPAH) is associated with mutations in bone morphogenetic protein receptor II (BMPRII). The role of this mutation in vascular tone and structural remodelling in PAH is unknown. The aim of this thesis was.to determine the ability of BMPRII ligands to modulate the ET-1 system, which has been implicated in the p'athogenesis of FPAH. BMP2, BMP4 and BMP? were examined for their effects on ET-1 release by cultured pulmonary artery smooth muscle cells (PASMC). BMP? (100ng/ml) significantly reduced cytokine-induced ET-1 release. BMP2 and BMP4 had no effect on ET-1 release from these cells. The influence of BMPRII ligands on vascular tone in normal PA has not been investigated. Ring segments of PA setup in organ baths, were assessed for their response to ET-1 in the presence and absence of 1, 10 or 100nglml of BMP2, BMP4 and BMP? BMP? significantly inhibited contraction in response to ET-1 in a concentration-dependent manner. This effect was not seen with BMP2 and BMP4. It has been suggested that mature vascular. endothelium can give rise to SMCs . via a process called endothelial to mesenchymal transformation (EMT). l(llmunocytochemistry and western blotting showed that TGF-J3 induced EMT in PA endothelial cells (PAEC) was associated with decreased VE-cadherin and zonula occludens expression and a loss of EC morphology. BMP? was able to restore the expression of these proteins as well as the EC phenotype. In addition, this study also demonstrates BMPRII ligands are able to produce these effects via Smad protein signalling in PASMC and PAECs. These results suggest that BMP? may have a'role in regulating ET-1 release and ET-1 induced contraction in the normal pulmonary circulation. BMP? also maintains the morphology of PAECs. Genetic mutations in BMPRII may lead to a loss of these regulatory mechanisms and contribute to the pathogenesis and vascular remodelling associated with FPAH.
Supervisor: Not available Sponsor: Not available
Qualification Name: University of London, 2008 Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.486283  DOI: Not available
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