Beniamen, Daniella M (2015) Cardiomyocyte overexpression of the α1A-AR induces enhanced myocardial angiogenesis via a paracrine mechanism. Masters thesis, Victor Chang Cardiac Research Institute & Clinical School - St Vincent's Hospital, Faculty of Medicine, UNSW.
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Abstract
The alpha (1A)-adrenergic receptors (α1A-ARs) play a pivotal role in regulating cardiac contractility. However direct evidence for their action on myocardial microvasculature is not known. Myocardial angiogenesis has generated great interest for its potential as a therapeutic alternative in the treatment of ischaemic disorders. Current pro-angiogenic therapies aim to instigate de novo formation of microvessels with the potential of reversing myocardial injury due to ischaemia, although the underlying mechanistic role is yet to be elucidated. To examine this we investigated the angiogenic role of the α1A-AR in mice with cardiac-specific transgenic (TG) α1A-AR overexpression (66-fold). At baseline, α1A-AR transgenic adult mice displayed enhanced angiogenesis within the myocardium compared to their non-transgenic littermates (NTLs) through up-regulated VEGF-A mRNA expression in isolated cardiomyocytes (CMs), and increased myocardial capillary density. This study investigates the mechanistic role implicating α1A-ARs expressed specifically on CMs in stimulating angiogenesis through VEGF-A and thereby enhancing myocardial perfusion. At 24 hours and 7-days post-myocardial infarction (MI) performed by occlusion of the left anterior descending artery (LAD), infarct size and CM apoptosis was markedly reduced, whereas CM proliferation was increased in α1A-AR TG mice, indicating a delay in left ventricular remodelling and increase in CM viability. Capillary density also increased in the infarct, border and remote zones of α1A-AR TG mice subjected to MI for 7 days compared to NTLs, suggesting a cross-talk between CMs and endothelial cells (ECs) promotes neo-angiogenesis that favourably enhances myocardial perfusion to areas under ischaemic stress. Utilizing an In vitro model, human umbilical vein endothelial cells (HUVECs) were treated with cultured CM conditioned medium from either α1A-AR TG mice or NTLs with or without the α1A-AR agonist A61603. We reported an A61603-dependent increase in HUVEC tubule formation on matrigel and increased VEGF-A mRNA expression in α1A-AR CMs receiving 25nM A61603 treatment compared to NTLs. Thus increased vessel formation suggests that the paracrine mechanism of action between CMs and ECs is initiated by VEGF-A up-regulation due to α1A-AR stimulation. Our data reveal the α1A-AR to be capable of activating EC migration, sprouting and maturation within the cardiac microenvironment, such that is necessary for enhanced myocardial perfusion.
| Item Type: | Thesis (Masters) |
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| Additional Information: | SUPERVISOR: Dr Poornima Balaji, Clinical School - Prince of Wales Hospital, Faculty of Medicine, UNSW COPYRIGHT/LICENSING: This work can be used in accordance with the Creative Commons BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 03 May 2016 04:05 |
| Last Modified: | 03 May 2016 04:05 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/433 |
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