Abstract
The aging population is rapidly growing. Aging is associated with impaired angiogenesis –the growth of new blood capillaries‐ and contributes to the increased susceptibility to various diseases. Thus, in order to develop more efficient therapies for aging‐associated diseases, we need to understand the mechanisms by which aging impairs angiogenesis. In addition to soluble angiogenic factors, biophysical factors such as changes in cell size and geometry control endothelial cell (EC) growth and differentiation. Here we have found that pulmonary artery ECs in aged mice are significantly larger than those in young mice. Aged human adipose tissue ECs are also larger than those in young adults. A major focal adhesion protein, paxillin, distributes at the distal ends of actin stress fibers in young mouse ECs, while paxillin is localized along the actin fibers in the cytoplasm in aged ECs. A Hippo signaling transducer, Yes‐associated protein (YAP1), acts as a mechanosensitive transcriptional co‐activator and controls organ development and regeneration. YAP1 also regulates angiogenesis. The levels of YAP1 decrease and EC proliferation is inhibited in ECs isolated from aged mouse lungs. To analyze whether age‐related changes in EC size control YAP1 activity, we cultured ECs on the microcontact‐printed substrates consisting of square fibronectin‐coated single‐cell sized islands. When we culture aged lung ECs on large islands of size comparable to aged mouse lung EC, YAP1 is excluded from the nucleus and EC proliferation is attenuated. Reduction of the aged EC size by culturing on smaller islands restores YAP1 nuclear localization and EC proliferation. These results suggest that age‐dependent increases in EC size impair aged EC proliferation through YAP1 signaling. Modulation of aged EC size and subsequent stimulation of YAP1 activity could restore the age‐related decline in angiogenesis and would be a promising strategy for aging‐associated diseases.Support or Funding InformationNIHR21AG054830, AHA18TPA34170129, MCW Research Affair Committee New Investigator AwardThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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