Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 654

triggers a paracrine pathway in monocytes that depends on both TNF α and IL1 β ,

as well as ERK, JNK, and P38MAPK signaling pathways and NF κ B transcription

factor.

10.6.14 Gasotransmitters Hydrogen Sulfide and Nitric Oxide

Hydrogen sulfide belongs with nitric oxide and carbon monoxide to the gasotrans-
mitter family. It is synthesized from

L cysteine mainly by cystathionine

γ -lyase

(CSE), as well as cystathionine -synthase (CBS) and 3-mercaptopyruvate sulfur-

transferase in both endothelial and smooth muscle cells. It stimulates angiogenesis.
It stimulates the proliferation of vascular endothelial cells, but impedes that of
vascular smooth myocytes (cell type-specific effect).
Hydrogen sulfide and nitric oxide cause S-sulfhydration and S-nitrosylation,
respectively. S-sulfhydration converts cysteine SH group to hydropersulfide, thereby
increasing protein activity [ 1325 ]. On the other hand, S-nitrosylation of cysteine can
decrease protein activity.
However, during ischemia, NO modulates angiogenesis via S-nitrosylation of
various proteins. In particular, VEGF stimulates NO liberation from endothelial
cells, as it increases NOS3 expression and phosphorylation. Conversely, NO via
the sGC-cGMP axis reinforce this signaling, as it heigthens VEGF and FGF2
expression. In addition, NO supports endothelial cell migration, as it stimulates the
production of

β

α V β 3 -integrin, and raises FGF2-mediated degradation of extracellular
matrix by MMP13 and MMP14 peptidases.
In vascular smooth myocytes, H 2 S-mediated relaxation results from activation
of ATP-sensitive potassium channel (K AT P )[ 1326 ](Table 10.16 ). Hydrogen sulfide
signals via mitogen-activated protein kinase modules to activate ERK1 and ERK2,
JNK1 and JNK2, and P38MAPK. 75
In vitro, hydrogen sulfide (H 2 S) enhances angiogenic potential of endothelial
cells, as it improves cell proliferation, migration, and tube formation [ 1327 ]. Hy-
drogen sulfide operates via K AT P channels and increases phosphorylation of PKB,
ERK, and P38MAPK kinases in endothelial cells. Stimulation of endothelial cells
by vascular endothelial growth factor heightens H 2 S release. Therefore, endothelial
H 2 S production is involved in the pro-angiogenic VEGF effect. Hydrogen sulfide
promotes the proliferation of endothelial cells, but primes apoptosis in smooth
myocytes, as does nitric oxide. It also causes the phosphorylation of the regulator
HSP27 of cell migration by mitogen-activated protein kinase-activated protein
kinase (MAPKAPK), a P38MAPK substrate.
Hydrogen sulfide and nitric oxide are mutually required in vascular endothelial
cells to trigger angiogenesis (hence proliferation and migration of endothelial cells)

75 Hydrogen sulfide activates ERK1 and ERK2 in monocytes, smooth myocytes, and gastric
epithelial cells [ 1327 ]. It stimulates P38MAPK in smooth muscle and β cells, but precludes

P38MAPK phosphorylation in neutrophils and microglial cells.