Research Paper|Volume 11, Issue 17|pp 7051—7069

Effects of age-dependent changes in cell size on endothelial cell proliferation and senescence through YAP1

Tadanori Mammoto¹, Yu-Suke Torisawa^5,⁶, Megan Muyleart¹, Kathryn Hendee¹, Charles Anugwom¹, David Gutterman^2,³, Akiko Mammoto^1,⁴

¹Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA
²Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI 53226, USA
³Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
⁴Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
⁵Hakubi Center for Advanced Research, Kyoto University, Kyoto 615-8540, Japan
⁶Department of Micro Engineering, Kyoto University, Kyoto 615-8540, Japan

Received: April 13, 2019Accepted: August 21, 2019Published: September 5, 2019

https://doi.org/10.18632/aging.102236

Copyright © 2019 Mammoto et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Angiogenesis – the growth of new blood capillaries- is impaired in aging animals. Biophysical factors such as changes in cell size control endothelial cell (EC) proliferation and differentiation. However, the effects of aging on EC size and the mechanism by which changes in cell size control age-dependent decline in EC proliferation are largely unknown. Here, we have demonstrated that aged ECs are larger than young ECs and that age-dependent increases in EC size control EC proliferation and senescence through CDC42-Yes-associated protein (YAP1) signaling. Reduction of aged EC size by culturing on single-cell sized fibronectin-coated smaller islands decreases CDC42 activity, stimulates YAP1 nuclear translocation and attenuates EC senescence. Stimulation of YAP1 or inhibition of CDC42 activity in aged ECs also restores blood vessel formation. Age-dependent changes in EC size and/or CDC42 and YAP1 activity may be the key control point of age-related decline in angiogenesis.