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.
Highlights
Angiogenesis plays important roles in organ development, regeneration and pathology [1, 2]
There was no significant difference in the actin stress fiber structures in young vs. old endothelial cell (EC) (Figure 1B), a major focal adhesion protein, paxillin, which was localized in the punctate form at the distal ends of actin stress fibers in young adipose ECs, was distributed along the actin fibers in the cytoplasm in aged ECs (Figure 1B)
Consistent with others’ reports [46, 47], EC proliferation measured by BrdU nuclear incorporation was lower by 69% in ECs isolated from aged human adipose tissue, while cellular senescence detected by P16INK4A immunocytochemical (ICC) analysis and SA-β galactosidase (Gal) staining increased in aged human adipose ECs; the intensity of P16INK4A and SA-βGalpositive cells increased by 2.2- and 10.7-times in aged vs. younger human ECs (Figure 1C)
Summary
Angiogenesis plays important roles in organ development, regeneration and pathology [1, 2]. Stiffness, and blood flow play important roles in angiogenesis [6, 7]. Culturing ECs on substrates of different stiffness or at the different densities changes cell size and shape, and modulates angiogenic gene expression and regulates EC proliferation, behaviors, and function [9,10,11]. ECM stiffness [12] and blood flow [5], which change cell size and shape, are altered in aged tissues with epithelial cells and fibroblasts being generally larger than those in younger tissues [13,14,15,16]. The direct effects of EC size on age-dependent changes in EC www.aging-us.com proliferation and suppression of angiogenesis have not been explored
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