Zhiyong Lei1, Alain van Mil1, Maarten M. Brandt2, Sebastian Grundmann3, Imo E. Hoefer1, Michiel Smits1, Hamid el Azzouzi1, Takanori Fukao4, Caroline Cheng5,2, Pieter A. Doevendans1,6, Joost P. G. Sluijter1,6
1Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands
2Experimental Cardiology, Erasmus Medical Center, Rotterdam, The Netherlands
3Department of Cardiology and Angiology I, University Heart Center Freiburg - Bad Krozingen, Freiburg, Germany
4Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
5Division Nephrology & Hypertension University Medical Center Utrecht Utrecht The Netherlands
6ICIN, Netherlands Heart Institute, Utrecht, The Netherlands
Tóm tắt
AbstractArteriogenesis is a complicated process induced by increased local shear‐and radial wall‐stress, leading to an increase in arterial diameter. This process is enhanced by growth factors secreted by both inflammatory and endothelial cells in response to physical stress. Although therapeutic promotion of arteriogenesis is of great interest for ischaemic diseases, little is known about the modulation of the signalling cascades via microRNAs. We observed that miR‐132/212 expression was significantly upregulated after occlusion of the femoral artery. miR‐132/212 knockout (KO) mice display a slower perfusion recovery after hind‐limb ischaemia compared to wildtype (WT) mice. Immunohistochemical analysis demonstrates a clear trend towards smaller collateral arteries in KO mice. Although Ex vivo aortic ring assays score similar number of branches in miR‐132/212 KO mice compared to WT, it can be stimulated with exogenous miR‐132, a dominant member of the miR‐132/212 family. Moreover, in in vitro pericyte‐endothelial co‐culture cell assays, overexpression of miR‐132 and mir‐212 in endothelial cells results in enhanced vascularization, as shown by an increase in tubular structures and junctions. Our results suggested that miR‐132/212 may exert their effects by enhancing the Ras‐Mitogen‐activated protein kinases MAPK signalling pathway through direct inhibition of Rasa1, and Spred1. The miR‐132/212 cluster promotes arteriogenesis by modulating Ras‐MAPK signalling via direct targeting of its inhibitors Rasa1 and Spred1.
