Endothelial TDP-43 controls sprouting angiogenesis and vascular barrier integrity, and its deletion triggers neuroinflammation

TDP-43 is a DNA/RNA-binding protein that regulates gene expression and its malfunction in neurons has been causally associated with multiple neurodegenerative disorders. Although progress has been made in understanding the functions of TDP-43 in neurons, little is known about its role in endothelial cells (ECs), angiogenesis and vascular function. Using inducible EC-specific TDP-43 knockout mice, we show that TDP-43 is required for sprouting angiogenesis, vascular barrier integrity and blood vessel stability. Postnatal EC-specific deletion of TDP-43 leads to retinal hypovascularization due to defects in vessel sprouting associated with reduced EC proliferation and migration. In mature blood vessels, loss of TDP-43 disrupts the blood-brain barrier and triggers vascular degeneration. These vascular defects are associated with an inflammatory response in the central-nervous system with activation of microglia and astrocytes. Mechanistically, deletion of TDP-43 disrupts fibronectin matrix around sprouting vessels and reduces ?-catenin signaling in ECs. Together, our results indicate that TDP-43 is essential for the formation of a stable and mature vasculature. Overall design: The RNA Sequencing analysis was performed using endothelial cells (EC) from the spinal cord of control and EC-specific knock-out mice at postnatal day 16. TDP-43 gene deletion was inducied via tamoxifen injection every 24 hours and three times at P5-P7,. Three animals were used per experimental group.