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

Aging (Albany NY). 2019 Sep 5;11(17):7051-7069. doi: 10.18632/aging.102236. Epub 2019 Sep 5.

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.

Keywords: aging; angiogenesis; cell proliferation; cell size; senescence.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Adult
  • Aging / physiology*
  • Animals
  • Cell Cycle Proteins / metabolism*
  • Cell Size
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Female
  • Humans
  • Male
  • Mice, Inbred C57BL
  • Middle Aged
  • Neovascularization, Physiologic
  • Primary Cell Culture
  • Transcription Factors / metabolism*
  • cdc42 GTP-Binding Protein / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Yap1 protein, mouse
  • cdc42 GTP-Binding Protein