Abstract
The functional properties of the vascular endothelium are diverse and heterogeneous between vascular beds. This is especially evident when new blood vessels develop from a pre-existing closed cardiovascular system, a process termed angiogenesis. Endothelial cells are key drivers of angiogenesis as they undergo a highly choreographed cascade of events that has both exogenous (e.g., hypoxia and VEGF) and endogenous regulatory inputs. Not surprisingly, angiogenesis is critical in health and disease. Diverse therapeutics target proteins involved in coordinating angiogenesis with varying degrees of efficacy. It is of great interest that recent work on non-coding RNAs, especially long non-coding RNAs (lncRNAs), indicates that they are also important regulators of the gene expression paradigms that underpin this cellular cascade. The protean effects of lncRNAs are dependent, in part, on their subcellular localization. For instance, lncRNAs enriched in the nucleus can act as epigenetic modifiers of gene expression in the vascular endothelium. Of great interest to genetic disease, they are undergoing rapid evolution and show extensive inter- and intra-species heterogeneity. In this review, we describe endothelial-enriched lncRNAs that have robust effects in angiogenesis.
Highlights
The cardiovascular system is a complex and dynamic network of blood vessels pumping blood from the heart to the rest of the body
spliced-transcript endothelialenriched lncRNA (STEEL) functions as a rheostat of angiogenesis that responds to shear stress conditions. They identified a long non-coding RNAs (lncRNAs)-protein interaction that presents a new mechanism for genomic targeting of the polyADP ribosylase 1 (PARP1), which contributes to transcriptional regulation, DNA damage repair, and cardiovascular disease (Chaudhuri and Nussenzweig, 2017)
Using RNA pulldown followed by mass spectrometry and RNA Immunoprecipitation (RIP) to identify and confirm this interaction, respectively, and Chromatin immunoprecipitation (ChIP) to demonstrate an effect of STEEL knockdown on PARP1 occupancy at the endothelial nitric oxide synthase (eNOS) and KLF2 promoters
Summary
The cardiovascular system is a complex and dynamic network of blood vessels pumping blood from the heart to the rest of the body. These independent cis-DNA elements, namely the SSRE, KLF and MEF2 elements mediate transcriptional responses to changes in shear stress Adding to this classic cis-trans paradigm, EC gene expression is regulated by epigenetic mechanisms. Nuclear lncRNAs like XIST or HOTAIR are often important mediators of regulating epigenetic mechanisms (Mercer et al, 2009) They can act in cis or in trans by interacting with neighboring or non-neighboring genes to exert their effects (Rinn et al, 2007; Wang et al, 2011; Engreitz et al, 2013; Novikova et al, 2013). To identify chromatin associated lncRNAs, approaches have been broadly classified into either “one-to-many” or “all-to-all.” One-to-many approaches include
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