Mechanosensory Pathways in Angiocrine Mediated Tissue Regeneration - Mechanical and Chemical Signaling in Angiogenesis - page 28

VEGFR2 is part of a mechanosensory complex, comprised of Platelet Endothelial
Cell Adhesion Molecule 1 (PECAM-1) (which transmits mechanical force), vas-
cular endothelial cell cadherin (VE-cad), beta-catenin (which acts as an adaptor),
and VEGFR2 (which activates phosphatidylinositol-3-OH kinase) [ 42 ]. This
complex is sufficient to confer responsiveness to shear stress induced by flow in
heterologous cells. Mechanical activation of VEGFR2 enables it to recruit PI3-
kinase, and therefore mediates the activation of Akt and endothelial nitric oxide
synthase (eNOS). Blocking the receptor activity in these complexes leads to a
significantly diminished response to mechanical stress in endothelial cells.
Therefore, a correctly assembled complex is indispensable to form a sensing
mechanotransduction mechanism.
3.5 Regulation of MicroRNA's by Biomechanical Forces
MicroRNAs (miRNAs) are small noncoding RNA molecules (21-25 nucleotides)
that function as post-transcriptional regulators by binding to complementary
sequences on target mRNA transcripts [ 43 , 44 ]. This usually results in translational
repression, target degradation, or gene silencing [ 45 ]. Approximately 30 % of
human protein coding genes are estimated to be regulated by miRNAs. The role of
miRNAs in various biological processes, in both health and disease, is becoming
more evident. These processes include cell proliferation and differentiation,
angiogenesis [ 46 - 48 ], and cardiovascular homeostasis [ 49 , 50 ]. The role of
miRNA in endothelial cell (EC) biology was shown by studying the various
knockdowns of key molecules in miRNA biogenesis (such as Dicer, and Drosha).
EC Dicer knockouts studied in vitro showed changes in the expression of genes
involved in EC biology, as well as reduced EC proliferation and angiogenesis [ 51 ].
ECs with knockdown of both Dicer and Drosha had significant reduction in cap-
illary sprouting and tube forming activity [ 52 ]. Therefore, an overall reduction of
miRNAs (via knockdown of Dicer and/or Drosha) significantly affects EC func-
tions in vitro and in vivo, which indicates miRNAs might have an important role in
regulating angiogenesis and vascular function [ 43 , 44 , 52 , 53 ]. EC gene expression
in response to pulsatile shear flow indicated that miRNAs (specifically miR-12b)
play an important regulatory role in the inhibition of EC proliferation by pulsatile
shear stress [ 54 ]. Additionally, when the influence of shear stress on aortic arch
vessels was investigated, it was found that a flow-induced genetic pathway was
necessary for angiogenic sprouting. This pathway requires the production of
mechanosensitive zinc finger transcription factor (klf2a) that induces an EC-spe-
cific miRNA (mir-126) to activate VEGFR signaling [ 55 ]. This is yet another
example of miRNAs facilitating integration of a physiological stimulus using
growth factor signaling in ECs to guide angiogenesis.