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Extracellular RNA released due to shear stress controls natural bypass growth by mediating mechanotransduction

Manuel Lasch, Eike Christian Kleinert, Sarah Meister, Konda Kumaraswami, Judith-Irina Buchheim, Tobias Grantzow, Thomas Lautz, Sofia Salpisti, Silvia Fischer, Kerstin Troidl, Ingrid Fleming, Anna M. Randi, Markus Sperandio, Klaus T. Preissner and Elisabeth Deindl

Key Points

  • Shear stress induced release of RNA from endothelial cells is crucial for initiation of arteriogenesis by controlling mechanotransduction

  • Extracellular RNA is essential for vWF release from endothelial cells initiating the inflammatory process driving arteriogenesis

Abstract

Fluid shear stress in the vasculature is the driving force for natural bypass growth, a fundamental endogenous mechanism to counteract the detrimental consequences of vascular occlusive disease such as stroke or myocardial infarction. This process referred to as arteriogenesis relies on local recruitment of leukocytes, which supply growth factors to pre-existing collateral arterioles enabling them to grow. Although several mechanosensing proteins have been identified, the series of mechanotransduction events resulting in local leukocyte recruitment are not understood. In a mouse model of arteriogenesis (femoral artery ligation) we found that endothelial cells release RNA in response to increased fluid shear stress and that administration of RNase Inhibitor blocking plasma RNases improved perfusion recovery. In contrast, treatment with bovine pancreatic RNase A or human recombinant RNase1 interfered with leukocyte recruitment and collateral artery growth. Our results indicated that extracellular RNA (eRNA) regulated leukocyte recruitment by engaging vascular endothelial growth factor receptor 2 (VEGFR2), which was confirmed by intravital-microscopical studies in a murine cremaster model of inflammation. Moreover, we found that release of von Willebrand factor (vWF) due to shear stress is dependent on VEGFR2. Blocking VEGFR2, RNase application or vWF deficiency interfered with platelet-neutrophil aggregate formation, which is essential for initiating the inflammatory process in arteriogenesis. Taken together, the results show that eRNA is released from endothelial cells in response to shear stress. We demonstrate this extracellular nucleic acid as critical mediator of mechanotransduction by inducing the liberation of vWF, thereby initiating the multistep inflammatory process responsible for arteriogenesis.

  • Submitted May 1, 2019.
  • Revision received August 15, 2019.
  • Accepted August 27, 2019.