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Exploration of physiological and pathophysiological implications of miRNA-143 and miRNA-145 in cerebral arteries

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Subarachnoid haemorrhage (SAH), is a type of haemorrhagic stroke with a high short-term mortality rate and leads to cognitive impairments that reduce the quality of life of the majority of patients. The miRNA-143/145 cluster is highly expressed in vascular smooth muscle cells (VSMC) and has been shown to be necessary for differentiation and function, as well as an important determinant for phenotypic modulation/switching of VSMCs in response to vascular injury. We aimed to determine if miRNA-143 and miRNA-145 are important regulators of phenotypical changes of VSMCs in relation to SAH, as well as establishing their physiological role in the cerebral vasculature. We applied qPCR to study ischemia-induced alterations in the expression of miRNA-143 and miRNA-145, for rat cerebral vasculature, in an ex vivo organ culture model and an in vivo subarachnoid haemorrhage model. To determine the physiological importance, we did myograph studies on basilar and femoral arteries from miRNA-143/145 KO mice. miRNA-143 and miRNA-145 are not upregulated in the vasculature following our subarachnoid haemorrhage model, despite the upregulation of miR-145 in the organ culture model. Regarding physiological function, miRNA-143 and miRNA-145 are very important for general contractility in cerebral vessels in response to depolarization, angiotensin II and endothelin-1. Applying an anti-miRNA targeting approach in SAH does not seem to be a feasible approach, as miRNA-143 and miRNA-145 are not upregulated following SAH. The KO mouse data suggest that targeting miRNA-143 and miRNA-145 would lead to a general reduced contractility of the cerebral vasculature and unwanted dedifferentiation of VSMCs.

OriginalsprogEngelsk
TidsskriftJournal of Cardiovascular Pharmacology
Vol/bind74
Udgave nummer5
Sider (fra-til)409-419
ISSN0160-2446
DOI
StatusUdgivet - nov. 2019

ID: 58348620