Faculty, Staff and Student Publications
Publication Date
12-1-2024
Journal
Journal of Biological Chemistry
Abstract
The functional and structural integrity of the endothelium is essential for vascular homeostasis. Loss of barrier function in quiescent and migratory capacity in proliferative endothelium causes exuberant vascular permeability, a cardinal feature of many inflammatory diseases including acute lung injury (ALI). However, the signals governing these fundamental endothelial cell (EC) functions are poorly understood. Here, we identify mechanistic target of rapamycin (MTOR) as an important link in preserving the barrier integrity and migratory/angiogenic responses in EC and preventing lung vascular injury and mortality in mice. Knockdown of MTOR in EC altered cell morphology, impaired proliferation and migration, and increased endocytosis of cell surface vascular endothelial (VE)-cadherin leading to disrupted barrier function. MTOR-depleted EC also exhibited reduced VE-cadherin and vascular endothelial growth factor receptor-2 (VEGFR2) levels mediated in part by autophagy. Similarly, lungs from mice with EC-specific MTOR deficiency displayed spontaneous vascular leakage marked by decreased VE-cadherin and VEGFR2 levels, indicating that MTOR deficiency in EC is sufficient to disrupt lung vascular integrity and may be a key pathogenic mechanism of ALI. Indeed, MTOR as well as VEGFR2 and VE-cadherin levels were markedly reduced in injured mouse lungs or EC. Importantly, EC-targeted gene transfer of MTOR complementary DNA, either prophylactically or therapeutically, mitigated inflammatory lung injury, and improved lung function and survival in mouse models of ALI. These findings reveal an essential role of MTOR in maintaining EC function, identify loss of endothelial MTOR as a key mechanism of lung vascular injury, and show the therapeutic potential of EC-targeted MTOR expression in combating ALI and mortality in mice.
Keywords
Animals, TOR Serine-Threonine Kinases, Mice, Cadherins, Vascular Endothelial Growth Factor Receptor-2, Humans, Antigens, CD, Endothelial Cells, Lung, Acute Lung Injury, Cell Movement, Capillary Permeability, Autophagy, Human Umbilical Vein Endothelial Cells, Mice, Knockout, Cell Proliferation, endothelial cells, lung vascular injury, MTOR, gene therapy, VE-cadherin, VEGFR2
DOI
10.1016/j.jbc.2024.107952
PMID
39510184
PMCID
PMC11664419
PubMedCentral® Posted Date
11-6-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
