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Exploration of Physiological and Pathophysiological Implications of miRNA-143 and miRNA-145 in Cerebral Arteries

Christensen, Simon Topp MSc*; Johansson, Sara Ellinor PhD*; Warfvinge, Karin PhD*,†; Braun, Thomas Dr Dr habil; Boettger, Thomas Dr rer nat; Edvinsson, Lars PhD, MD*,†; Haanes, Kristian Agmund PhD*

Journal of Cardiovascular Pharmacology: November 2019 - Volume 74 - Issue 5 - p 409–419
doi: 10.1097/FJC.0000000000000735
Original Article
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Abstract: Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke with a high short-term mortality rate which 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 whether 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 quantitative PCR 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 SAH model. To determine the physiological importance, we did myograph studies on basilar and femoral arteries from miRNA-143/145 knockout mice. miRNA-143 and miRNA-145 are not upregulated in the vasculature following our SAH 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 because miRNA-143 and miRNA-145 are not upregulated following SAH. The knockout 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.

*Department of Clinical Experimental Research, Copenhagen University Hospital, Rigshospitalet-Glostrup, Denmark;

Division of Experimental Vascular Research, Department of Clinical Sciences, Lund University, Lund, Sweden; and

Department Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.

Reprints: Simon Topp Christensen, MSc, Glostrup Research Institute, Nordstjernevej 42, 2600 Glostrup, Denmark (e-mail: simon.topp.christensen.01@regionh.dk).

Supported by the Lundbeck foundation, Lundbeck Grant of excellence [no. R59-A5404], the Swedish Heart Lung Foundation [no. 20130271], and the KA Wallenberg foundation [no. KAW 2016.0081]. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors report no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jcvp.org).

Received April 12, 2019

Accepted July 20, 2019

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