We found that genetic or pharmacological induction of angiogenesis leads to cell-cycle arrest in a significant proportion of angiogenic endothelial cells (Pontes-Quero et al., 2019 Nature Communications). This occurs because endothelial cells exhibit a bell-shaped response to mitogenic stimuli. At high levels of VEGF or mitogenic ERK signaling, endothelial cells migrate and sprout but do not effectively proliferate. We intend to identify the mechanisms causing this intrinsic cell-cycle arrest to target it therapeutically when inducing angiogenesis. We envision this as the best way to effectively promote angiogenesis in ischemic tissues.

Arteries are formed by the specification and mobilization of capillary endothelial cells during angiogenesis, a process called arterialization. We have observed that this requires Notch signaling activity, the master regulator of arterialization, and the timely suppression of the cell cycle (Luo et al., 2021 Nature). Arterialization involves integration of numerous genetic and biophysical signals. Our department aims to quantitatively dissect the genetic and biophysical components that regulate arterialization. This knowledge will be crucial for effectively inducing this process. Another goal is to induce arterialization in quiescent or injured organs and assess its potential benefits for overall cardiovascular function.