LRP5 in age-related changes in vascular and alveolar morphogenesis in the lung

Abstract

Aging is associated with impaired angiogenesis and lung alveolar regeneration, which contributes to the increased susceptibility to chronic lung diseases (CLD). We have reported that the Wnt ligand co-receptor, low-density lipoprotein receptor-related protein 5 (LRP5), stimulates angiogenesis and lung alveolar regeneration. However, the role of LRP5 in age-related decline in vascular and alveolar morphogenesis remains unclear. In this report, we have demonstrated that vascular and alveolar structures are disrupted in the 24-month (24M) old mouse lungs. The expression of LRP5 and the major angiogenic factors, VEGFR2 and Tie2, is lower in endothelial cells (ECs) isolated from 24M old mouse lungs compared to those from 2M old mouse lungs. Vascular and alveolar formation is attenuated in the hydrogel implanted on the 24M old mouse lungs, while overexpression of LRP5, which restores angiogenic factor expression, reverses vascular and alveolar morphogenesis in the gel. Compensatory lung growth after unilateral pneumonectomy is inhibited in 24M old mice, which is reversed by overexpression of LRP5. These results suggest that LRP5 mediates age-related inhibition of angiogenesis and alveolar morphogenesis. Modulation of LRP5 may be a novel intervention to rejuvenate regenerative ability in aged lung and will lead to the development of efficient strategies for aging-associated CLD.

P53 in the impaired lungs

“…Aged lungs are prone to infectious diseases due to decreased mucociliary clearance, impaired innate and adaptive immunity [ [81] , [82] , [83] , [84] , [85] , [86] , [87] , [88] ]. In mouse pneumonia models, the cytokines and chemokine levels were higher in aged mice [ 85 ].…”

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

“…Angiogenesis is impaired in the aged mouse lungs [51]. YAP1 and CDC42 sense the age-dependent changes in EC size and control EC senescence (Figures.…”

“…For example, mechanosensitive transcription factors (e.g., TFII-I, GATA2, TWIST1) control angiogenesis and EC integrity, and contribute to angiogenesis-related diseases ( e.g., pulmonary fibrosis, pulmonary hypertension) [9, 60, 61]. Wnt co-receptor LRP5, which controls YAP1/TAZ activity [62], mediates ECM stiffness-induced Tie2 expression in ECs, and modulates lung development and age-dependent inhibition of post-PNX lung growth by changing angiogenesis [51, 63]. The expression of TWIST1 is regulated by YAP1 [64] and controls cellular senescence [65].…”

Case Control Association Study of WNT Signaling Pathway-related Genes and Osteoporosis Risk Among Chinese Postmenopausal Women

“…Low-density lipoprotein receptor-related protein 5 (LRP5) is located on chromosome 11q13.4 and encodes a WNT receptor that regulates osteoblastic activity and bone mass [28]. LRP5 is also related to glucose and cholesterol metabolism, and thus, LRP5 is involved in the development of metabolic diseases, such as diabetes, obesity and vascular diseases [29]. Moreover, numerous studies have indicated that the LRP5 gene in uences BMD and fracture [30].…”