Vascular stability is crucial to normal tissue homeostasis, but impaired in many common, but difficult to care diseases like sepsis, diabetic retinopathy and cancer. Our group is focused on indentifying mechanisms that can stabilize or destabilize the vasculature in disease, with the aim to develop these findings towards translational benefit.
Increased capillary leakage and endothelial inflammation can lead to organ failure and shock in sepsis and systemic inflammation. Vascular leakage and new vessel growth (angiogenesis) enhance solid tumor growth and metastasis and impair vision in common ocular diseases including diebetic retinopathy, diabetic macular edema and wet-age related macular degeneration. Drugs targeting the vascular endothelial growth factor (VEGF) have entered in clinical use to block angiogenesis in cancer and neovascular eye disease, whereas tools for vascular stabilization and prevention of capillary leakage in sepsis are scarce (Nat Rev Drug Disc, 2017, review).
Angiopoietin growth factors in the vasculature
Our group has interest on Angiopoietin (Angpt or Ang) growth factors that regulate vascular functions, including vessel stability and growth during development and tissue homeostasis (Cell, 2017; Clin Sci, 2017, reviews). Angiopoietins (Ang1 and Ang2) signal via the endothelial Tie (Tie1 and Tie2) receptor tyrosine kinases. Recent studies by our group have identified mechanisms by which the Ang-Tie system destabilizes blood vessels during inflammation, leading to vascular leakage (J Clin Invest, 2016).
Integrins couple endothelial cells to the underlying vascular basement membrane, thereby participating in vascular growth and vessel stability. Recent studies by our group have identified signaling interactions between the angiopoeitin-Tie system and integrins that impair endothelial integrity (Nat Commun, 2015; PNAS, 2018).