Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 659

coronary obstructions, by endogenous bypasses. Endothelial precursor cells can be
seen in adult blood. However, they are less efficient than umbilical cord blood-
derived cells. The transplantation of cord blood-derived endothelial progenitor cells
enhances neovascularization [ 1337 ]. Transplantation of L-selectin

+ ,VEGFR2 +

cells increases capillary density in ischemic tissues, via VEGFa release [ 1338 ].
During ischemia, endothelial PKA-NOS3 pathway promotes neovascularization.
The PKA-NOS3 pathway indeed regulates endothelial cell survival, proliferation,
and migration, tubulogenesis, relaxation and proliferation of vascular smooth
myocytes, and recruitment and differentiation of endothelial progenitor cells, or
circulating pro-angiogenic cells, to promote vasculogenesis.
Hypoxia and concurrent acidic pH foster the production of angiogenic factors,
such as VEGF and placental growth factors, chemokines (e.g., CCL2 and CXCL12),
and endothelial cell adhesion molecules (e.g., PECAM1). In addition, hypoxia
provokes recruitment and homing to ischemia sites of endothelial progenitor
cells [ 1339 ].
Protein kinase-A and -B are major regulators of NOS3 activation. The VEGF-
VEGFR2 complex stimulates PKA and PKB, hence NOS3 enzyme. Produced nitric
oxide primes the sGC-cGMP-PKG axis and subsequently the Ras-Raf-ERK1/2
cascades [ 1339 ]. Moreover, the PKA-NOS3 pathway interacts with the PI3K-
PKB-NOS3 (NOS3 activation), AMPK-NOS3 (NOS3 activity enhancement), and
PLC-PKC-NOS3 (NOS3 inactivation) axes.
In fact, numerous stimuli that influence NOS3 activation, hence NO synthesis,
by activated PKA, are activators of neovascularization. They comprise vasoactive
substances, such as bradykinin, prostaglandin-E2, and prostacyclin, in addition to
growth factors such as VEGF [ 1339 ].
Moreover, nitric oxide mediates angiogenesis and arteriogenesis primed by
neuropeptide-Y during ischemia via activation of NOS3 and upregulation of VEGF
and PDGF expression [ 1339 ].
Nitrite (NO 2 ) and nitrate (NO 3 ) anions are not only metabolites resulting
from NO oxidation, but also represent an alternative NO source to synthesis that
maintains NO availability. Dietary or endogenous nitrate are converted into nitrite
in the digestive tract; nitrate is reduced to nitrite by oral commensal bacteria
(Vol. 4 - Chap. 10. Other Major Signaling Mediators). Nitrite can be reduced to
NO by deoxyhemoglobin, deoxymyoglobin, xanthine oxidoreductase, ascorbate,
polyphenols, and protons, under PKA stimulation [ 1339 ]. In addition, adenosine-
dependent NOS3 can be activation by the ACase-PKA axis.
Both NADPH oxidase and uncoupled NOS3 are plasma membrane-bound ROS
synthases. 79 Reactive oxygen species at low levels can regulate vascular growth and
remodeling. Hypoxia-stimulated NADPH oxidase promotes VEGF production via
JunB, activation of PKB, ERK1, and ERK2, and subsequent angiogenesis [ 1339 ].

79 NADPH oxidase also localizes to the endoplasmic reticulum. Mitochondria are another major
ROS sources.