Pericyte Requirement for Anti-Leak Action of Angiopoietin-1 and Vascular Remodeling in Sustained Inflammation

Abstract

Blood vessel leakiness is an early, transient event in acute inflammation but can also persist as vessels undergo remodeling in sustained inflammation. Angiopoietin/Tie2 signaling can reduce the leakiness through changes in endothelial cells. The role of pericytes in this action has been unknown. We used the selective PDGF-B-blocking oligonucleotide aptamer AX102 to determine whether disruption of pericyte-endothelial crosstalk alters vascular leakiness or remodeling in the airways of mice under four different conditions: i) baseline, ii) acute inflammation induced by bradykinin, iii) sustained inflammation after 7-day infection by the respiratory pathogen Mycoplasma pulmonis, or iv) leakage after bradykinin challenge in the presence of vascular stabilization by the angiopoietin-1 (Ang1) mimic COMP-Ang1 for 7 days. AX102 reduced pericyte coverage but did not alter the leakage of microspheres from tracheal blood vessels at baseline or after bradykinin; however, AX102 exaggerated leakage at 7 days after M. pulmonis infection and increased vascular remodeling and disease severity at 14 days. AX102 also abolished the antileakage effect of COMP-Ang1 at 7 days. Together, these findings show that pericyte contributions to endothelial stability have greater dependence on PDGF-B during the development of sustained inflammation, when pericyte dynamics accompany vascular remodeling, than under baseline conditions or in acute inflammation. The findings also show that the antileakage action of Ang1 requires PDGF-dependent actions of pericytes in maintaining endothelial stability.

ROS-induced endothelial stress contributes to pulmonary fibrosis through pericytes and Wnt signaling

“…A Andersson-Sjöland et al that inflammation may result in loss of microvascular pericyte coverage, 27,28 however as the inflammatory response in our model was relatively modest, this appeared unlikely. Yet, to investigate pericytes closer, we studied tissue from controls and 2w (when inflammation peaks) using TEM.…”

Opposing actions of angiopoietin-2 on Tie2 signaling and FOXO1 activation

“…To assess vascular leakage, 50 μl of a suspension of 50-nm fluorescent polystyrene microspheres (1% solids, Bangs Laboratories, Inc.) was injected into the tail vein (36). Mice were anesthetized at 5 minutes and perfused after the microspheres circulated for 10 minutes.…”

“…Activating mutations in the Tie2 gene, transgenic overexpression, or administration of exogenous ANG1 or ANG2 alone can all induce vascular enlargement (30)(31)(32)(33)(34). The enlarged vessels have superficial similarities to leak-prone venules, but are resistant to leakage induced by inflammatory mediators (31,32,(35)(36)(37).…”

Lung Pericytes and Resident Fibroblasts

“…2,3,5,19,44 Furthermore, the endothelial-pericyte dependence on PDGF-B to prevent vascular leakage increases during sustained lung inflammation and is required for angiopoietin-1 (Ang-1) to help stabilize the endothelium. 49 Paracrine signaling by Ang-1 from pericytes through its receptor Tie-2 on endothelial cells generates a reciprocal interaction to the PDGF pathway. Ang-1 matures and stabilizes the endothelium, increasing its integrity, and also enables new blood vessels to sprout and grow without leaking.…”