Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology
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Cellular and Molecular Life Sciences
REVIEW
Endothelial sprouting, proliferation, or senescence: tipping the balance from physiology to pathology Severin Mühleder1 · Macarena Fernández‑Chacón1 · Irene Garcia‑Gonzalez1 · Rui Benedito1 Received: 9 July 2020 / Revised: 5 September 2020 / Accepted: 1 October 2020 © The Author(s) 2020
Abstract Therapeutic modulation of vascular cell proliferation and migration is essential for the effective 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 beneficial for angiogenesis, since it leads to an increase in both endothelial proliferation and sprouting. However, several recent studies showed that an increase in mitogenic stimuli can also lead to the arrest of angiogenesis. 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 effectively 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 effects on this balance and on vascular cells. Here, we review the main findings 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 effectiveness of pro-angiogenic therapies in cardiovascular regenerative medicine. Keywords Endothelial cells · Senescence · Cell-cycle arrest · Sprouting · Vascular differentiation · Malformations
Introduction In mammalian cells, highly complex and regulated processes involving a plethora of signals monitor the initiation, sustainment, and termination of cell division and migration. Due to its importance for tissue development, maintenance, and regeneration, several molecular mechanisms and checkpoints exist to regulate and balance these two morphogenetic processes. Through the regulation of cellular proliferation, the building blocks of a tissue are formed, while migration is essential to distribute those blocks in space, to give a tissue its ultimate shape and function. It is often difficult to dissociate the effect of genes or pathways on cell proliferation versus cell sprouting or migration in vivo. As a simple example, if the migration of cells towards a given growth factor niche is inhibited, proliferation will be indirectly also * Rui Benedito [email protected] 1
Molecular Genetics of Angiogenesis Group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, 28029 Madrid, Spain
affected, since the cells will not be able to occupy areas of high growth factor bioavailability. On the other hand, if proliferation and f
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