Abstract 1632: Tie2-Deficient Mice Exhibit Increased Susceptibility to Endothelial Apoptosis, Arteriolar Muscularization, and Pulmonary Arterial Hypertension in Response to Interleukin-6

Abstract

Introduction: We have demonstrated downregulation in lung Tie2 receptor expression and activity in experimental models of PAH, implicating reduced Tie2 survival signaling in the pathogenesis of this disease. Therefore, we hypothesized that Tie2 deficiency would predispose to PAH due to increased endothelial cell (EC) apoptosis in response to environmental triggers. Methods: Adult male Tie2± or littermate WT mice received saline or interleukin-6 (IL-6) at a rate of 200ng/kg/day via subcutaneous injections for 1 or 2 weeks. Results: Significant elevation in RVSP (Fig.1 ) was observed in IL-6 treated Tie2± mice (31 ± 3mmHg) compared to saline-treated Tie2 ± mice (25 ± 1mmHg) and IL-6 treated WT mice (22 ± 1mmHg). Following 1 week of IL-6 treatment, increased pulmonary microvascular EC apoptosis was observed by TUNEL in Tie2± mice compared to WT (6.3 ± 0.3% vs. 0.9 ± 0.1%, respectively; p < 0.01). Furthermore, after 2 weeks, a significant increase in pulmonary microvascular muscularization by SMA staining (Fig.2 ) was seen in IL-6 treated Tie2±/mice compared to WT (36.4 ± 1.5% vs. 22.5 ± 1.1%, respectively; p < 0.01). Interestingly, Western blot analysis revealed a significant decrease in Angiopoietin-1 (Ang-1) level in the lung after 2 weeks of IL-6 treatment in Tie2± mice, and ELISA demonstrated a 60% decrease in Ang-1 secretion in vitro after incubation of pulmonary artery smooth muscle cells with IL-6 (p < 0.01). Conclusions: Tie2± mice demonstrated enhanced susceptibility to pulmonary EC apoptosis, increased muscularization, and PAH following chronic exposure to IL-6, supporting an important protective role for endogenous Tie2 signaling in the lung microvasculature. Figure 1. Increased RVSP in Tie2 +/+ mice following 2 weeks of IL-6 treatment (*P < 0.05 compared to Saline Tie2 +/+ ; † P < 0.01 compared to IL-6 WT) Figure 2. Increased pulmonary microvascular muscularization in Tie2 +/+ mice following 2 weeks of IL-6 treatment.