Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 639

phosphorylates (activates) LIMK1 kinase, 51 that, in turn, inactivates cofilin, an
actin-severing factor required in cell migration [ 1267 ]. 52
Actin-binding proteins filamin-A and -B are synthesized in endothelial cells. 53
Filamin-B intervenes in endothelial cell migration [ 1270 ]. The signaling cas-
cade includes filamin-B, Rac1, its downstream effectors P21/CDC42/Rac-activated
kinases PAK4 to PAK6 and guanine nucleotide-exchange factor Vav2.
Upon activation of VEGFR2, Src kinase phosphorylates Vav2 to stimulate Rac
GTPase. Activated Rac activates its effector P21-activated kinase that phospho-
rylates cadherin-5 associated with VEGFR2 receptor. Phosphorylated cadherin-5 P
recruits and binds β -arrestin-2 involved in endocytosis via clathrin-coated vesicles.

β -Arrestin-2 attracts Src near cadherin-5 for phosphorylation of cadherin-catenin

complexes. Factor VEGF hence promotes cadherin-5 endocytosis and disassem-
bling of intercellular adherens junctions to disrupt the endothelium [ 1271 ].

Mediators of VEGF Synthesis

Nitric oxide favors VEGF synthesis. Expression of VEGF is stimulated by growth
factors and mitogens as well as hypoxia. It is also regulated by many transcriptional
regulators.
Hypoxia stimulates several transcription factors, such as hypoxia-inducible
factor (mainly), cAMP-response element-binding protein, early growth response
EGR1, metal response element (MRE)-binding transcription MTF1, 54

κ

NF B, and

activating enhancer-binding protein AP1. 55

α

Under hypoxic conditions, HIF1 is

α β

activated by the PI3K-PKB and ERK pathways. Factor HIF1 -HIF1 stimulates

glycolysis and angiogenesis [ 1272 ].
Transcription factors NF

κ

B and Activator protein AP1 are often activated
by the same stimuli to target common genes. Hypoxia-inducible factor targets
NF

κ

B that stimulates AP1 subunit JunB that is required for basal and hypoxia-
induced activation of VEGF transcription (Fig. 10.2 )[ 1273 ]. 56 The latter targets

β β

core-binding factor- (non-DNA-binding CBF ) that forms with Runt-related

α

transcription factor Runx (CBF ) the core-binding heterodimeric transcription

51 Kinase LIMK1 is also phosphorylated by RoCK and PAK, downstream from Rho GTPases.
52 Cofilin phosphatases slingshot and chronophin dephosphorylate (activate) cofilin. Overexpres-
sion of LIMK1 suppresses cell motility [ 1268 , 1269 ].
53 Filamin-A, the most abundant, is widespread, whereas filamin-B, also broadly expressed, is
produced mainly in endothelial cells. Filamin-C is primarily expressed in skeletal myocutes.
54 A.k.a. metal-regulatory transcription factor-1 (MTF1).
55 The AP1 family is composed of dimeric protein complexes formed by products of Jun, Fos, and
ATF gene families. Hypoxia upregulates AP1 expression that activates target genes for endothelin-
1 and PDGFb in endothelial cells.
56 Hypoxia-responsive transcription factor JunB is activated by numerous stimuli, such as NF κ B
and inflammatory cytokines. Other AP1 subunits Jun and Fos act as partners of VEGF response to
hypoxia.