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Endothelial Senescence in Regenerative Lung Growth after Pneumonectomy
Author(s) -
Mammoto Akiko,
Hendee Kathryn,
Mammoto Tadanori
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04355
Subject(s) - senescence , angiogenesis , lung , regeneration (biology) , pneumonectomy , biology , cancer research , medicine , pathology , immunology , microbiology and biotechnology
Impairment of lung regeneration and repair in aging animals contributes to the pathogenesis of aging‐associated diseases, including chronic obstructive pulmonary disease (COPD). Angiogenesis – the formation of new blood capillaries ‐ plays a key role in organ regeneration. We have reported that inhibition of angiogenesis attenuates lung growth after unilateral pneumonectomy (PNX) and that post‐PNX regenerative lung growth is inhibited in aged mice. While accumulation of senescent cells in aged adults is linked to the age‐related decline in regenerative ability, senescent cells also play important roles in injury repair and tissue remodeling. Here we investigate the role of endothelial cell (EC) senescence in regenerative lung growth after PNX in young vs. aged mice. The levels of the senescence marker, p16 INK4A and a major angiogenic factor, angiopoietin2 (Ang2) transiently increase in ECs isolated from 2‐months (2M) old post‐PNX mouse lungs compared to those from sham‐operated control mice and decrease at the later stage. The baseline levels of p16 INK4A are high in 24M old mouse lung ECs but post‐PNX transient induction of p16 INK4A and Ang2 is inhibited in 24M old mouse lung ECs. Depletion of senescent cells from 2M old p16‐3MR mice by treating with ganciclovir suppresses post‐PNX lung growth. When ECs isolated from 2M old post‐PNX mouse lungs are mixed in the gel and implanted on the mouse lungs, vascular network formation is stimulated in the gel, while these effects are inhibited in the gel mixed with 24M old post‐PNX mouse lung ECs. These results suggest that post‐PNX transient induction of EC senescence is required for vascular morphogenesis after PNX. Deregulation of this mechanism may contribute to age‐dependent inhibition of regenerative lung growth. Understanding this mechanism will lead to the development of efficient strategy for aging‐associated lung diseases. Support or Funding Information NIH R21AG054830, NIH R21AG062893, NIH R01HL142578, AHA 18TPA34170129