Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 629

this promoter heightens 100-fold after exercise, whereas the transcription from the
proximal promoter remains constant [ 1227 ].

10.6.2.7 Kr uppel-like Factor

Kr uppel-like factor KLF2 is produced in mature endothelial cells subjected to both
shear stress and statins as well as circulating pro-angiogenic cells, formerly called
endothelial progenitor cells, at a comparable level [ 1228 ]. It provokes endothelial
functional differentiation. In mature endothelial cells, KLF2 prevents angiogenesis.
During senescence, KLF2 level decays [ 1228 ]. In aged mice, numbers of cir-
culating SCA1 endothelial-

committed progenitor cells lower. Moreover, KLF2 expression drops in spleen- and
bone marrow-derived circulating pro-angiogenic cells.

+ ,SCFR + ,Lin − progenitors and SCA1 + ,VEGFR2 +

10.6.2.8 Hypoxia-Inducible Factor

Hypoxia-inducible factor HIF1 intervenes in the compensatory angiogenesis to
insufficient O 2 supply. It initiates gene expression for numerous angiogenic regula-
tors, vessel remodeling, as well as recruitment of bone marrow-derived, circulating
angiogenic cells.
This ubiquitous, heterodimeric transcription factor mediates adaptive responses
to hypoxia and ischemia. Isotype HIF1 is made of O 2 -regulated HIF1 α and

constitutively expressed HIF1 β subunits. Subtype HIF2 α is an HIF1 α paralog.

Under hypoxia, HIF1 α translocates to the nucleus, dimerizes with HIF1 β , and binds

to hypoxia response elements (HRE).
Transcriptional activity of HIF1 functions on genes that encode vascular endothe-
lial (VEGF), placental (PlGF), and platelet-derived (PDGF) growth factors, stem
cell factor, angiopoietin-2, and CXCL12 chemokine. These angiogenic factors bind
to their cognate receptors (VEGFR1 and VEGFR2 for VEGF; VEGFR1 for PlGF;
PDGFR for PDGFB; SCFR for SCF; TIE2 for Ang2, and CXCR4

for CXCL12) in the plasma membrane of vascular endothelial cells, pericytes, and
smooth myocytes.
In addition, HIF1 regulates the expression of hundreds of genes that encode,
in particular, plasmalemmal receptors of angiogenic cytokines and homing signals
for the recruitment of pro-angiogenic cells, such as endothelial progenitor cells,
hematopoietic stem and progenitor cells, and mesenchymal stem cells, in addition
to bone marrow-derived myeloid cells [ 1229 ].

α and PDGFR β

HIF in Pulmonary Arterioles

Whereas systemic arterioles dilate in response to local tissue hypoxia to increase O 2
delivery, pulmonary arterioles constrict in response to hypoxia to ensure proper local