Human microvascular pericyte basement membrane remodeling regulates neutrophil recruitment.

Abstract

Neutrophil extravasation at post-capillary venules, consisting of EC, PC, and the shared ECM, increases following fibrotic remodeling in the lung, liver, and skin. The role of fibrotic pericyte-derived ECM in regulating EC activation and neutrophil recruitment remains unexplored. To elucidate the role of human pericyte-derived ECM in EC activation, we characterized PC-derived ECM following transforming growth factor-β1, IL-1β, CCL2, or bleomycin activation, and examined surface adhesion molecule expression and neutrophil recruitment by EC cultured on PC-ECM. Pro-inflammatory activation of PC-induced deposition of compositionally distinct ECM compared with non-activated control. Bleomycin activation induced fibronectin-rich and collagen-poor ECM remodeling by PC, facilitating increased neutrophil transendothelial migration when compared with non-activated pericyte ECM (49.9±3.4% versus 29.7±1.4%). Increases in fibronectin compared to collagen I, are largely responsible for ECM-regulated neutrophil recruitment, as EC cultured on fibronectin supported increased neutrophil transmigration compared to collagen I (51.6±6.2% versus 28.0±4.8%). We attribute this difference to increased expression of ICAM-1 and its redistribution to EC borders. This is the first demonstration of human pericyte sensitivity to inflammatory stimuli, inducing fibrotic matrix deposition that regulates EC adhesion molecule expression and neutrophil recruitment.