microRNA-200b as a Switch for Inducible Adult Angiogenesis

Abstract

Significance: Angiogenesis is the process by which new blood vessels develop from a pre-existing vascular system. It is required for physiological processes such as developmental biology and wound healing. Angiogenesis also plays a crucial role in pathological conditions such as tumor progression. The underlying importance of angiogenesis necessitates a highly regulated process.

Recent advances: Recent works have demonstrated that the process of angiogenesis is regulated by small noncoding RNA molecules called microRNAs (miRs). These miRs, collectively referred to as angiomiRs, have been reported to have a profound effect on the process of angiogenesis by acting as either pro-angiogenic or anti-angiogenic regulators.

Critical issues: In this review, we will discuss the role of miR-200b as a regulator of angiogenesis. Once the process of angiogenesis is complete, anti-angiogenic miR-200b has been reported to provide necessary braking. Downregulation of miR-200b has been reported across various tumor types, as deregulated angiogenesis is necessary for tumor development. Transient downregulation of miR-200b in wounds drives wound angiogenesis.

Future directions: New insights and understanding of the molecular mechanism of regulation of angiogenesis by miR-200b has opened new avenues of possible therapeutic interventions to treat angiogenesis-related patho-physiological conditions. Antioxid. Redox Signal. 22, 1257-1272.

FIG. 1.

Noninvasive techniques to study angiogenesis postwounding. Images depict porcine burn wound at day 14 (early time point) and day 42 (late time point). (A) Laser speckle image showing blood perfusion in wound area. The dashed rectangle in laser speckle image represents the initial wound area. Scale bar indicates the gradient from high to low perfusion. (B) The wound depth and blood vessels can be visualized from the three-dimensional ultrasound image (43). The feeder blood vessels are in red. The scale bar indicates the gradient of in flow and out flow of blood. (C) The healing of wound can be accessed by elastography. The scale bar indicates the hardness and softness of tissue. The region within the arrows represents wound bed. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

miRs are transcribed in the nucleus by RNA Polymerase II/III. The initial transcript (pri-miRNA) is processed in the nucleus by RNA endonuclease Drosha to form pre-miRNA. Pre-miRNA is exported to the cytosplasm where it is cleaved by Dicer to form mature miRNA and subsequently loaded on to RISC complex for its function. The RNA-induced silencing complex (RISC) comprises argonaute (AGO), Tar RNA-binding protein (TRBP), and other proteins. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 3.

Mechanism of translational repression by miRs. miRs bound to RISC complex on pairing with mRNA could lead to ribosomal drop-off, translational initiation blockage or decapping or degradation of mRNA. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 4.

Angiogenesis during fetal development and in adult dermal wounds shares a common platform based on their miR expression pool. The expression level of miRs in the wound edge tissue during the initial stage of healing is lower compared with that in the post-healing phase. Low miR abundance facilitates angiogenesis during development as well as in the repair phase. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 5.

Chromosomal location and sequence of miR-200 family. The mature miR-200b is processed from the 3′- arm of pre-miR-200b. The sequence is conserved in mice and humans across members of the miR-200 family. The chromosomal location of humans is shown in green, while that of mice is indicated in red. The seed sequence of miR-200 family members has been highlighted in yellow. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 6.

miR 200b expression in skin during prenatal, postnatal, and adult stage. Injury transiently suppresses miR200b expression for angiogenesis to occur postwounding. The inability to suppress miR-200b expression in patho-physiological conditions such as diabetes leads to impaired angiogenesis. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 7.

Schematic representation showing miR-200b downstream targets. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 8.

Interaction between miR-200b and GATA. (A) Homeostatis, (B) during the early stage of wound healing, miR-200b is attenuated, which leads to increased abundance of GATA protein and facilitates angiogenesis, and (C) during impaired wound healing, proinflammatory TNF-α leads to induction of miR-200b, which, in turn, suppresses GATA levels, thus impairing angiogenesis. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars