Characterization of p38 Inflammatory Response in Human Brain Vascular Pericyte Cells

Abstract

G protein-coupled receptor (GPCR) mediated mitogen activated protein kinase (MAPK) p38 activation is a crucial regulator of pro-inflammatory and pro-angiogenic responses. Prior studies have revealed an atypical pathway for p38 activation that induces auto-phosphorylation of p38 through the direct binding of transforming growth factor β activated kinase 1 binding protein-1 (TAB1) in endothelial cells. During angiogenesis and inflammation, endothelial cells are known for their rapid proliferation, migration, and expression of cytokines. Pericyte cells serve to guide these endothelial cells, modulating vascular stability and orchestrating vascular inflammatory responses. During inflammation, pericytes migrate away from the vasculature leaving endothelial tubules exposed and fragile. Atypical p38 activation has not yet been examined in pericyte cells. We hypothesize that atypical p38 signaling regulates G protein-coupled receptor-mediated vascular function through control of pericyte signaling. Our preliminary data shows for the first time that a family of GPCR ligands, including thrombin and histamine, can activate p38 via the atypical p38 signaling pathway in primary human brain vascular pericytes. Chemical inhibition and siRNA depletion of TAB1-TAB2 abrogates inflammatory signaling by brain pericyte cells. As the role of GPCR induced p38 signaling in pericytes has not been examined, our current studies focus on defining this role, including establishing a co-cultured model of pericyte and endothelial cells. Using this model, we are the first to define atypical p38 signaling in pericyte cytokine expression, migration, and endothelial vascular formation. These studies represent an unexplored branch of neurovascular inflammatory signaling, which we predict is a critical driver of neurovascular disease.