Apoptosis regulates endothelial cell number and capillary vessel diameter but not vessel regression during retinal angiogenesis

Abstract

The growth of hierarchical blood vessel networks occurs by angiogenesis. During this process, new vessel growth is accompanied by the removal of redundant vessel segments by selective vessel regression ('pruning') and a reduction in endothelial cell (EC) density in order to establish an efficient, hierarchical network. EC apoptosis has long been recognised for its association with angiogenesis, but its contribution to this process has remained unclear. We generated mice in which EC apoptosis was blocked by tissue-specific deletion of the apoptosis effector proteins BAK and BAX. Using the retina as a model, we found that apoptosis made a minor contribution to the efficiency of capillary regression around arteries where apoptosis was most concentrated, but was otherwise dispensable for vessel pruning. Instead, apoptosis was necessary for the removal of non-perfused vessel segments and the reduction in EC density that occurs during vessel maturation. In the absence of apoptosis, increased EC density resulted in an increase in the diameter of capillaries, but not arteries or veins. Our findings show that apoptosis does not influence the number of vessels generated during angiogenesis. Rather it removes non-perfused vessel segments and regulates EC number during vessel maturation, which has vessel-specific consequences for vessel diameter.

CCN1–Yes-Associated Protein Feedback Loop Regulates Physiological and Pathological Angiogenesis

“…3L). This is consistent with the finding of Watson et al that apoptosis does not influence the number of vessels generated during angiogenesis (22). Vascular sprouts of UB-ΔYAP mutant retinas were characterized by the appearance of short stubs with blunted edges lacking filopodial extensions (Fig.…”

Influence of Radiotherapy Fractionation Schedule on the Tumor Vascular Microenvironment in Prostate and Lung Cancer Models

“…Indeed, Chen et al have seen decreased vessel density in a similar context. Also, endothelial cell death is not necessary detrimental to blood vessel function below a certain extent [27]. Contrary to normal tissues where regrowth is absent, we presume that endothelial destruction after RT may not systematically translate into long-lasting effects in tumors.…”

YAP and TAZ regulate adherens junction dynamics and endothelial cell distribution during vascular development

“…During sprouting angiogenesis, the arrangement and distribution of cells rather than their numbers appear to drive morphogenesis of the vascular tree. Recent data showing unaltered remodelling in the absence of endothelial cell apoptosis and normal branching frequency across a range of endothelial cell densities support this idea (1). In the extreme, however, too few cells will jeopardize network formation and stability (2), whereas too many cells might compromise vessel calibre control (1).…”

“…Recent data showing unaltered remodelling in the absence of endothelial cell apoptosis and normal branching frequency across a range of endothelial cell densities support this idea (1). In the extreme, however, too few cells will jeopardize network formation and stability (2), whereas too many cells might compromise vessel calibre control (1). Functional network formation therefore needs to establish the right number of cells in the right place, and distribute them such that the hierarchical branching pattern is supported.…”