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A collaborative paper from the De Val and Smart Groups has established multiple regulatory pathways responsible for the formation of blood vessels in the developing heart. In doing so they have identified a crucial pathway that is repressed in the adult heart after injury, which may hold the key to a new and improved strategy for repair.

Enhancer analysis tracks the formation of the coronary arteries during development

The growth of new blood vessels is crucially important for the repair of heart muscle after a heart attack. However, the adult heart is not capable of growing enough of the correct type of blood vessels after injury, which contributes to the damage sustained.

The reactivation of developmental pathways in the diseased heart is a long-term aim for cardiac regenerative medicine. However, the signalling and transcriptional pathways involved in coronary vessel development are not yet understood. It is also still unclear whether the processes regulating embryonic and neonatal coronary vessel growth in the healthy heart play any role during adult coronary vascular regeneration after damage.

In a paper published in Nature Communications, led by Associate Professors Sarah De Val and Nicola Smart, the research team have used a novel enhancer-led approach to identify the transcriptional pathways involved in the development of coronary vessels in the healthy heart. Their technique has allowed direct interrogation of the behaviour of these pathways after ischemic injury in both the regenerative neonatal heart and the non-regenerative adult heart. 

They have identified three different regulatory pathways in mice which direct the formation of blood vessels in the heart during development. Of these, the main pathway responsible for the formation of new blood vessels, the angiogenesis-associated VEGFA-MEF2 pathway, is active in the healthy adult heart but is repressed after heart injury.

 

The adult heart doesn't respond "appropriately" to myocardial infarction to repair its coronary vasculature using the pathways used in the embryo to build the vasculature, which are activated in the more regenerative neonatal heart following injury. With this insight, we're in a better position to start investigating why and how to target a more efficient repair
- Prof Smart

The hypothesis is that the blood vessels do not grow well enough to repair the damaged heart because the heart appears to be inhibiting the pathway that it most needs to be active in order to successfully heal. Their results suggest that reactivating this pathway may improve blood vessel growth after heart attack. They will use a recently awarded grant from the British Heart Foundation to determine if this is correct.

 

This paper identifies novel regulators of coronary vessel growth and reveals unsuspected variations in the mechanisms regulating coronary vessel growth depending on developmental stage and disease state, observations with significant implications to future strategies for cardiac regeneration. It also identifies a novel, druggable target for therapeutic manipulations of vascular growth in the adult ischemic heart. - Prof De Val

The full paperRegulatory pathways governing murine coronary vessel formation are dysregulated in the injured adult heart, is available to read here.

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