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

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.