Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.780628
Title: Neovascularisation of the heart post-MI : a role for endocardial trabeculation?
Author: Thomas, Tonia
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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Abstract:
Restoring blood flow after myocardial infarction (MI) is essential for the oxygenation of existing and newly regenerated tissue. Proangiogenic therapies have been previously investigated in an attempt to target existing coronary vessels, but with limited success. Endogenous vascular repair processes are poorly understood, therefore we sought to determine whether coronary vessel developmental mechanisms are intrinsically reactivated following injury in the adult mouse heart. Through pulse-chase genetic lineage tracing, we established that de novo vessel formation constitutes a significant component of the neovascular response and revealed that the endocardium is a major contributory source. During development, the endocardium contributes 60% of coronary vessels, this is in large part via compaction of the trabeculated endocardial surface perinatally. We have shown that the adult heart reverts to a hypertrabeculated state between one and five days post-MI and repeats the process of compaction from 7-14 days. This process appears to facilitate endocardium-derived neovascularization, leading to formation of mature sub-endocardial vessels after infarction. To gain insight into the mechanisms that regulate endocardium-derived vessel formation in the ischemic adult heart, we investigated candidate signalling pathways which orchestrate trabeculation and compaction during development. We observed reactivation of the Notch pathway in the endocardium following MI, in keeping with its role as a key regulator of these processes in development. Using Notch1 loss- and gain- of function mouse models targeted by an endothelial-specific Cre, we observed a hypertrabeculation response induced by constitutive Notch activity, and impaired trabeculation with reduced sub-endocardial vessels after disruption of Notch activity. Moreover, our data suggest a role for Notch in driving endothelial-mesenchymal transition (EndMT) to provide smooth muscle support to newly formed vessels. Insight into pathways that regulate endogenous vascular repair, and underlying mechanisms of transient hypertrabeculation and compaction, may reveal novel targets for therapeutically enhancing neovascularization in heart failure patients.
Supervisor: Smart, Nicola ; Rana, Amer Sponsor: British Heart Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.780628  DOI: Not available
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