Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 631

Table 10.13. MicroRNAs in angiogenesis (Source: [ 886 , 1235 ]; SpRED: Sprouty-related EVH1
domain-containing protein).

Type Targets

MicroRNA-92a Integrin- α 5 (repression of angiogenesis)

Sirtuin-1 (activation of Notch, repression of VEGF [?])

MicroRNA-126 PI3K r2 (derepression of the PI3K axis)

SpRED1 (derepression of the Raf1 axis)
IGFBP2 repression (inactivation of endothelial IGF1R)
Endothelial MerTK stimulation (cancer call MerTK inhibition)

MicroRNA-132 RasA1 (derepression of Ras GTPase)

and miR378, whereas anti-angiogenic microRNAs encompass miR15b, miR16,
miR92a, miR214, miR221, miR222, and miR328 [ 1232 ].
Dicer that produces final forms of microRNAs participates in postnatal angiogen-
esis induced by various stimuli. Growth factors can regulate microRNA expression.
Factor VEGF regulates the expression of several microRNAs, such as components
of the MyC cluster miR17-92 [ 1233 ].
Angiogenic sprouting of aortic arch vessels relies on the mechanosensitive
transcription factor Kr uppel-like factor KLF2a that provokes synthesis of
endothelial-specific miR126 to activate VEGF signaling [ 1234 ]. MicroRNA-126
represses Sprouty-related EVH1 domain-containing protein SpRED1 and PI3K r2
subunit, which prevent MAPK and PI3K signaling, respectively [ 886 ]. Therefore,
miR126 derepresses PI3K and cRaf axes to support VEGF-induced angiogenesis
(Table 10.13 ).
MicroRNA-132 suppresses RasA1, a RasGAP, in the endothelium, thereby
increasing Ras activity and promoting angiogenesis [ 1236 ]. Its expression is upreg-
ulated in a human embryonic stem cell model of vasculogenesis and in endothelia of
human tumors and hemangiomas, but is undetectable in normal endothelium. On the
other hand, RasA1 is produced in normal endothelium, but not tumor endothelium.
MicroRNAs encoded by the miR23-miR27-miR24 gene clusters 37 are involved
in cell cycle control, proliferation, and differentiation of various cell types. They
abound in endothelial cells. Their pro-angiogenic effect results from the repression
of the anti-angiogenic mediators Sprouty-2 and semaphorin-6A [ 1237 ].
Microvescicles represent a mode of communication between cancer and endothe-
lial cells to launch endothelial cell migration. MicroRNAs are indeed packaged into
and carried by microvescicles that can be taken up by endothelial cells. In cancer
cells, some microRNAs such as miR126 can impede recruitment of endothelial
cells [ 1235 ], whereas others such as miR9 are tumor promoters. In endothelial

37 Two miR23-miR27-miR24 clusters exist: an intergenic miR23a-miR27a-miR24-2 and intronic
miR23b-miR27b-miR24-1 cluster.