Vasculature Growth - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 647

APJ 68 on endothelial cells to regulate the lumen size of blood vessels. In vascular
endothelial cells, the synthesis of apelin and APJ is regulated during angiogenesis.
Under hypoxia, hypoxia inducible factor-1

binds to the hypoxia-responsive
element of the apelin gene and increases apelin expression in vascular cells [ 1293 ].
Expression of the apelin gene is high in tip cells to modulate proliferation of APJ

α

+

stalk cells.
The major signaling pathways of apelin are the Gq-PKC-ERK and Gi-PI3K-
PKB axes in APJ

endothelial cells. Both the PI3K-PKB-TOR pathway and
MAPK module lead to the phosphorylation of S6K kinase [ 1293 ]. The PI3K-
PKB pathway contributes to endothelial cell migration, whereas the ERK-S6K and
PI3K-S6K axes control endothelial cell proliferation.
During embryogenesis, APJ is expressed on endothelial cells of new blood
vessels sprouted from the dorsal aorta, but not on endothelial cells of the pre-existing
dorsal aorta. Apelin enhances endothelial cell proliferation primed by vascular
endothelial growth factor and promotes between-cell aggregation. In addition,
apelin may stabilize intercellular junctions between of endothelial cells.

+

Angiopoietin-like Molecules

Seven angiopoietin-like molecules exist (AngL1-AngL7). These pleiotropic
molecules are expressed by many cell types. Isoforms AngL2 to AngL4 and AngL6
are secreted and can then be detected in plasma. Angiopoietin-like molecules
regulate lipid, glucid, and energy metabolism. Angiopoietin-like molecules bind
neither to TIE1 nor TIE2 receptor. In endothelial cells, AngL1 to AngL4 and AngL6
contribute to the control of angiogenesis via survival and migration signals [ 1289 ].

10.6.6.2 Adrenomedullins

Adrenomedullin (Vol. 2 - Chap. 3. Growth Factors), as are VEGF, endothelin-
1 and -2, and angiogenin, is stimulated by hypoxia. Angiogenic adrenomedullin
tethers to its receptors calcitonin receptor-like receptor (CalcRL) connected to
receptor activity-modifying proteins RAMP2 and RAMP3 (Vol. 3 - Chap. 7.
G-Protein-Coupled Receptors) and activates protein kinase-B, mitogen-activated
protein kinase, and focal adhesion kinases in endothelial cells, especially during
acute ischemia [ 1294 ]. Moreover, adrenomedullin upregulates VEGF expression.
Intermedin, or adrenomedullin-2 (Adm2), is an angiogen. In cultured
endothelial cells, this growth factor provokes cell migration and tube formation.
Adrenomedullin-2 increases the phosphorylation of extracellular signal-regulated

have different receptor-binding affinities and activities. Apelin has a positive inotropic effect and
can cause vasoconstriction and vasodilation (via NO) according to circumstances.
68 Receptor APJ is widespread in embryos and adults, especially in the lung and heart, as well as in
vascular and endocardial endothelial and smooth muscle cells.