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A2880 - Vascular Endothelial Cell-Specific Connective Tissue Growth Factor (CTGF) Is Necessary for Development of Chronic Hypoxia-Induced Pulmonary Hypertension
Author Block: A. J. Bryant1, L. Pi2, C. Fu1, Y. Lu3, J. Zhou1, K. Lipson4, E. W. Scott5; 1Medicine, University of Florida College of Medicine, Gainesville, FL, United States, 2Pediatrics, University of Florida College of Medicine, Gainesville, FL, United States, 3Medicine, University of Florida, Gainesville, FL, United States, 4Fibrogen, San Francisco, CA, United States, 5Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, United States.
Introduction: Chronic-hypoxia frequently complicates the care of patients with interstitial lung disease, contributing to the development of pulmonary hypertension (PH), and premature death. Connective tissue growth factor (CTGF), a matricellular protein of the Cyr61/CTGF/Nov (CCN) family, is known to exacerbate vascular remodeling within the lung. We have previously demonstrated that vascular endothelial-cell specific down-regulation of CTGF is associated with protection against the development of PH associated with hypoxia, though the mechanism for this effect is unknown. Hypothesis: We hypothesize that endothelial CTGF is required for recruitment of circulating myeloid-cells to the lung, contributing to subsequent development of PH. Method: In this study, we generated a transgenic mouse with constitutive deletion of CTGF in vascular endothelial cells (“eCTGF KO” mice). We then exposed these mice, and controls, to either bleomycin-induced lung injury, or chronic hypoxia exposure. Results: Lack of vascular endothelial-derived CTGF protected against the development of PH secondary to chronic hypoxia, but not PH due to bleomycin-induced pulmonary fibrosis. Importantly, attenuation of PH was associated with a decrease in infiltrating inflammatory cells expressing CD11b, a known adhesion receptor for CTGF, in the lungs of hypoxia-exposed transgenic mice. Moreover, these pathological changes were associated with activation of Cdc42 signaling within endothelial cells leading to alteration in endothelial barrier function. Conclusions: These data indicate that endothelial-specific deletion of CTGF results in protection against development of chronic-hypoxia induced PH. This protection is conferred by both a decrease in inflammatory cell recruitment to the lung, and a reduction in lung endothelial barrier permeability. Based on our studies, CTGF inhibitor treatment should be investigated in patients with PH associated with chronic hypoxia secondary to chronic lung disease.