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Title: Endothelial progenitor cell responses to hypoxia : role of bone morphogenetic protein/gremlin signalling
Author: Ali, Imran Hussain Ahemad
ISNI:       0000 0004 5372 1821
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2014
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Endothelial progenitor cells (EPCs) are vascular stem cells which hold the ability to repair and or replace damaged vasculature. EPCs have already been shown to improve patient outcomes in myocardial infarction and limb ischemia. Before EPCs can be considered for therapeutic angiogenesis in patients, we first must fully understand how these cells function and respond to the hypoxia milieu that is ever present in diabetic complications. This study has found chronic hypoxia affects OEC function and drives OECs towards a stress induced premature senescence. Chronic hypoxia markedly reduced OEC proliferation, downregulated markers commonly associated with stem and progenitor cells, reduced Akt and several of its substrates activation with increased SA-p-gal activity. The mRNA of members of the BMP/Smad pathway were increased in response to hypoxia however, this was not reflected at the protein level. OECs only responded to rhBMP-7 treatment with activation of the canonical Smad pathway. Gremlin a BMP antagonist which is also involved limb, lung and kidney development has recently been implicated in angiogenesis. This thesis further supports Gremlins role in angiogenesis as we report an increase in VEGFR2 activation which enhanced OEC angiogenic potential through increased tube formation and migration in OECs with rhGremlin treatment. Since Gremlin is known to be essential in the limb, lung and kidney formation its potential involvement in eye and retinal vasculature development was determined through the generation of grem1-/- mice. Our data suggests Gremlin may not be critical in the eye and retina development as the eyes of grem1-/- mice were comparable to the wild type control mice. However, there was a slight decrease in the number of branching retinal vessels which suggests Gremlin may regulate the vascularisation of the retina. In summary, data in this thesis advances our understanding of OEC function under hypoxic conditions and highlights novel roles for BMP-7 and Gremlin in OEC biology and blood vessel formation.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available