Age-dependent modulation the microvasculature by human microenvironment and serum

The functional decline of the vascular niches is linked to several disorders, including neurodegeneration and bone loss. However, the causes of this decline are poorly understood. A key signature of aging is the progressive damage of the microvasculature, but a clear picture of its determinants and therapeutic targets in a human context is lacking. We designed/validated a novel approach based on long-living human microvascular networks to study the age-dependent modulation of the endothelium by microenvironment and serum. Young fibroblasts restored the barrier function of aged endothelial cells, an effect counteracted by old serum. Among the involved factors, ANGPTL4 played a key role in restoring cell-cell junctions and vascular barrier. Once validated, we employed this strategy to identify potential targets involved in the degeneration of the Blood Brain Barrier (BBB) in Alzheimer Disease (AD) patients. Using serum from AD as well as from age-matched healthy donors, we demonstrated that PTP4A3 played a critical role in the regulation of vascular permeability and that its inhibition restored the functionality of the BBB exposed to serum from AD patients. We believe our strategy will be an invaluable tool to identify and therapeutically modulate the aging signature of the endothelium in the context of age-related diseases. Overall design: Human skin endothelial cells were co-cultured with human fibroblasts from young or old donors. Human skin endothelial cells were also co-cultured with human fibroblasts from young donors and incubated with medium containing human serum from young or old donors. Human brain endothelial cells were co-cultured with human brain pericytes and astrocytes and incubated with serum from AD patients or age-matched healthy donors. Global gene expression changes were measured by mRNA-Seq in a paired design.