We have uncovered novel cellular mechanisms that maintain vascular stability during systemic inflammation and cancer metastasis. Additionally, we have identified new regulators of endothelial permeability, highlighting potential targets and pathways for future studies aimed at developing vascular-stabilizing therapies.
Our research revealed that inflammation increases endothelial permeability via the adhesion receptor beta1-integrin. Inhibiting this pathway in a preclinical LPS-induced endotoxemia model with blocking antibodies significantly reduced vascular leakage and protected against endotoxemia-induced cardiac failure. We demonstrated that beta1-integrin enhances endothelial cell tension and forms specialized cell-matrix adhesions, particularly under inflammatory conditions. This discovery offers new insights into the regulation of vascular permeability, which could inform therapeutic strategies for systemic inflammation.
Additionally, we identified a novel function for the oncogenic Pim3 kinase in maintaining endothelial cell-cell adhesion integrity. We discovered that PIM kinase inhibitors, originally developed for cancer trials, impaired vascular barrier integrity, leading to vascular leakage and increased cancer metastasis. These findings may explain the lack of efficacy seen with PIM inhibitors as anti-cancer drugs in clinical trials. Moreover, this opens new avenues to investigate the mechanisms through which Pim3 maintains the vascular barrier, with potential translational impact.
We also discovered a new reactive capillary endothelial cell type in the lung alveolus that increases in number during cancer metastasis. These cells, while expressing angiogenic markers characteristic to tumor vasculature, also express vascular protective genes, suggesting a role in maintaining lung homeostasis under stress, such as metastasis or inflammation. Given the critical role of the lung vascular barrier in various inflammatory diseases, where its dysregulation can lead to alveolar leakage, our findings open new avenues for research on translationally relevant research areas.
We additionally established a pipeline for recombinant protein production, purification, and structural analysis, enabling us to investigate endothelial growth factors and their receptors at the atomic level. Our results uncover novel mechanisms of growth factor signaling in endothelial cell-cell junctions, involving interactions with two distinct receptor classes: growth factor receptors and cell adhesion receptors. This work demonstrates how growth factor oligomerization and conformational changes in cell adhesion receptors spatially pattern growth factor signaling in the endothelium. These findings provide fundamental insights into receptor tyrosine kinases signaling, offering critical understanding of how these receptors regulate cellular processes in the vasculature.
