Vascular Endothelium - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 500

Neuroprotection is based on the neurovascular unit that includes neurons and
associated glial cells, vascular endothelium and support cells, and extracellular ma-
trix. Endothelial cells of the human brain microcirculation synthesize neuregulin-1.
Upon ligand binding, Nrg1 receptors HER2 and HER3 are phosphorylated and
trigger the PI3K-PKB, Ras-ERK, and JaK-STAT pathways to ensure cytoprotec-
tion, particularly during oxidative stress [ 926 ]. Because HER2 and HER3 lack
ligand-binding and efficient kinase activity, respectively, they form an active HER2-
HER3 heterodimer. Other Nrg1 mediators comprise phospholipase-C and protein

kinase-C. Neuregulin-1 enhances survival of endothelial cells and can contribute to
neuron survival during stroke. Furthermore, neuregulin-1 promotes angiogenesis.

γ

9.5.8.8 Histone Deacetylases - Epigenetic Control by Hemodynamic

Stress

Certain class-1 (i.e., HDAC1-HDAC3) and -2a (i.e., HDAC5 and HDAC7) histone
deacetylases are sustainably upregulated and accumulate in the nucleus in cultured
endothelial cells subjected to a low-steady-component pulsatile flow (modulation
rate 8) [ 927 ]. On the other hand, a high-steady-component pulsatile flow (modula-
tion rate 1/3) causes phosphorylation-dependent nuclear export of class-2a HDACs.
Histone deacetylases regulate the activity of NFE2-related factor NRF2 and
Kr uppel-like factor KLF2 that target many mechanical stress-responsive genes and
cell cycle. Transcription factor NRF2 binds to the anti-oxidant response element
(ARE) in promoters of many anti-oxidant genes.
Steady flow causes phosphorylation-dependent nuclear export of HDAC5, hence
its dissociation from myocyte enhancer factor MEF2, as well as expression of
anti-inflammatory Kr uppel-like factor KLF2 and endothelial nitric oxide synthase
(NOS3) via sirtuin-1 [ 927 ]. Nitric oxide-mediated nuclear shuttling of HDAC4 and
HDAC5 relies on the association of protein phosphatase PP2 with the phosphory-
lated calcium-calmodulin-dependent kinase CamK4 P -HDAC complex. Phosphor-
ylation of HDAC enzymes by CamK kinases causes HDAC export from the nucleus
and cytosolic sequestration by 14-3-3 proteins.
A low-steady-component pulsatile flow uses the PI3K-PKB pathway. It enables
the association of class-1 histone deacetylases with NRF2 and that of HDAC3 and
class-2a histone deacetylases with MEF2 [ 927 ]. Subsequently, NRF2 and MEF2 are
deacetylated, thus being unable to bind to ARE element. Consequently, expression
of anti-oxidant gene NAD(P)H quinone oxidoreductase-1 (NQO1) and KLF2 is
reduced. Moreover, this type of unsteady flow increases the production of cyclin-A,
but decreases that of CKI1a cyclin-dependent kinase inhibitor in endothelial cells,
thereby inducing their proliferation. In addition, inhibition of KLF2 expression
enables elevated VCAM1 production.
Because a high-steady-component pulsatile flow causes export of class-2a
HDACs from the nucleus, it precludes HDAC5/7-MEF2 association, thereby