TAK1 Prevents Endothelial Apoptosis and Maintains Vascular Integrity

TNF-alpha is apleiotropic cytokine that has the potential to induce apoptosis under inflammation. How endothelial cells (ECs) are spared from this fate in inflammatory environments where TNF-alpha is present is not known. Here, we show that TGF-beta-activated kinase 1 (TAK1) ensures EC survival and maintains vascular integrity upon TNF-alpha stimulation. Endothelial-specific TAK1 knockout mice exhibit intestinal and liver hemorrhage due to EC apoptosis, leading to vascular destruction and rapid death. This EC apoptosis was induced by TNF-alpha from myeloid cells responding to intestinal microbiota. TNF-alpha secretion associated with inflammation also induced vascular defects in inflamed organs. Additionally, we determined that TAK1 deletion in tumor ECs resulted in blood vessel and hence tumor regression. Our results illuminate mechanisms ensuring survival of intestinal and liver ECs under physiological conditions and ECs of other organs under inflammatory conditions that could be exploited for anti-angiogenic therapy to treat cancer.