Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology

Abstract

Therapeutic modulation of vascular cell proliferation and migration is essential for the efective inhibition of angiogenesis in cancer or its induction in cardiovascular disease. The general view is that an increase in vascular growth factor levels or mitogenic stimulation is benefcial for angiogenesis, since it leads to an increase in both endothelial proliferation and sprout ing. However, several recent studies showed that an increase in mitogenic stimuli can also lead to the arrest of angiogen esis. This is due to the existence of intrinsic signaling feedback loops and cell cycle checkpoints that work in synchrony to maintain a balance between endothelial proliferation and sprouting. This balance is tightly and efectively regulated during tissue growth and is often deregulated or impaired in disease. Most therapeutic strategies used so far to promote vascular growth simply increase mitogenic stimuli, without taking into account its deleterious efects on this balance and on vascular cells. Here, we review the main fndings on the mechanisms controlling physiological vascular sprouting, proliferation, and senescence and how those mechanisms are often deregulated in acquired or congenital cardiovascular disease leading to a diverse range of pathologies. We also discuss alternative approaches to increase the efectiveness of pro-angiogenic therapies in cardiovascular regenerative medicine.