Characterization of p38 Inflammatory Response in Human Pericytes

Abstract

G protein‐coupled receptor (GPCR) mediated mitogen activated protein kinase (MAPK) p38 activation is a crucial regulator of pro‐inflammation and pro‐angiogenic responses during chronic lung disease. Our studies have revealed an atypical (non‐canonical) 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. However, during angiogenesis, endothelial cells are known for their rapid reproduction, migration, and tubule formation. Pericyte cells serve to guide these endothelial cells, providing vascular stability and cytokine signaling. 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, but is hypothesized to play a key role in regulating G protein‐coupled receptor‐mediated control of vascular function. Very little is known about the cellular mechanisms that control atypical p38 activation, representing a novel therapeutic target. Our preliminary data shows that thrombin and histamine can activate p38 via the atypical p38 signaling pathway in primary human pericytes. 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 the role of atypical p38 signaling in pericytes, along with their vascular formation and function. These studies represent a novel approach to regulate vascular p38 activity, pro‐inflammatory signaling, and chronic lung disease, and this model will provide us with the tools necessary to identify the role of p38 induced inflammation in the migration of pericyte cells.