The Extraordinary Role of Extracellular RNA in Arteriogenesis, the Growth of Collateral Arteries

Abstract

Arteriogenesis is an intricate process in which increased shear stress in pre-existing arteriolar collaterals induces blood vessel expansion, mediated via endothelial cell activation, leukocyte recruitment and subsequent endothelial and smooth muscle cell proliferation. Extracellular RNA (eRNA), released from stressed cells or damaged tissue under pathological conditions, has recently been discovered to be liberated from endothelial cells in response to increased shear stress and to promote collateral growth. Until now, eRNA has been shown to enhance coagulation and inflammation by inducing cytokine release, leukocyte recruitment, and endothelial permeability, the latter being mediated by vascular endothelial growth factor (VEGF) signaling. In the context of arteriogenesis, however, eRNA has emerged as a transmitter of shear stress into endothelial activation, mediating the sterile inflammatory process essential for collateral remodeling, whereby the stimulatory effects of eRNA on the VEGF signaling axis seem to be pivotal. In addition, eRNA might influence subsequent steps of the arteriogenesis cascade as well. This article provides a comprehensive overview of the beneficial effects of eRNA during arteriogenesis, laying the foundation for further exploration of the connection between the damaging and non-damaging effects of eRNA in the context of cardiovascular occlusive diseases and of sterile inflammation.

RNase A Treatment Interferes With Leukocyte Recruitment, Neutrophil Extracellular Trap Formation, and Angiogenesis in Ischemic Muscle Tissue

“…The reduced accumulation of leukocytes in ischemic tissue of RNase A treated mice may, however, not only be a function of reduced leukocyte recruitment but also of reduced leukocyte extravasation. The expression of intracellular adhesion molecule 1 (ICAM1) on endothelial cells of post-capillary veins, which is a prerequisite for leukocyte transmigration and extravasation ( Ley et al, 2007 ), is also a function of the VEGF/VEGFR2 system and thus might be dependent on the availability of extracellular RNA ( Kluever et al, 2019 ).…”

“…This initiates a cascade of signaling events, which involves an activation of platelets and mast cells. As a result, neutrophils and monocytes are recruited, which promote vessel growth by supplying growth factor and cytokines (Chandraratne et al, 2015;Chillo et al, 2016;Kluever et al, 2019;Lasch et al, 2019a). Interestingly, administration of bovine RNase A as well as recombinant human RNase 1 significantly interfered with the process of arteriogenesis and leukocyte recruitment, whereas the administration of inactive human recombinant RNase or DNase had no effect pointing to the relevance of extracellular RNA in arteriogenesis (Lasch et al, 2019a).…”

Extracellular RNA as a Versatile DAMP and Alarm Signal That Influences Leukocyte Recruitment in Inflammation and Infection

“…These inflammatory agonists are recognized by neighboring tissue and immune cells to trigger the release of pro-inflammatory cytokines and chemokines, including IL-6, IFN-γ, and MCP-1 as described (Tay et al, 2020). In this context, exRNA as well could amplify this response, also by attracting leukocytes and other immune cells in a VEGF-receptor-2-dependent manner, as demonstrated in several preclinical studies (Fischer et al, 2012;Kluever et al, 2019;Lasch et al, 2019). In the ultimate phase of inflammation under physiological conditions, the attracted neutrophils and macrophages need to clear the site of infection/inflammation by phagocytosis and induce the final inflammatory step of resolution and recovery.…”

“…Yet, how these different steps all work together for blood vessel regeneration remained unanswered for a long time (Deindl and Schaper, 2005). Based on the recent findings that exRNA is liberated from shear stress-exposed endothelium, we hypothesized that exRNA may serve as a trigger and promoter of collateral vessel growth, including endothelial activation, leukocyte recruitment and cytokine release as well as stimulation of the VEGF signaling axis (Kluever et al, 2019; 2019; Figure 4).…”

From Increased Fluid Shear Stress to Natural Bypass Growth

“…For a long time, it was completely unknown how this increased mechanical stress results in local leukocyte recruitment promoting collateral artery growth. Co-workers of the group of Elisabeth Deindl describe the functional role of extracellular RNA in that process and highlight the role of this nucleic acid during ongoing arteriogenesis [3]. Moreover, the same group presents a simple flow cytometry-based method to identify and quantify tissue infiltrated leukocyte subpopulations [4].…”