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Front. Physiol. | doi: 10.3389/fphys.2018.00138

Vascular Endothelial Cell-Specific Connective Tissue Growth Factor (CTGF) is Necessary for Development of Chronic Hypoxia-Induced Pulmonary Hypertension

Liya Pi1, Chunhua Fu1, Yuanqing Lu1, Junmei Zhou1, Marda Jorgensen1,  Vinayak Shenoy2, Kenneth E. Lipson3, Edward W. Scott1 and  Andrew J. Bryant1*
  • 1University of Florida, United States
  • 2California Health Sciences University, United States
  • 3FibroGen (United States), United States

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. In this study, we generated a transgenic mouse line in which the Ctgf gene was floxed and deleted in vascular endothelial cells that expressed Cre recombinase under the control of VE-Cadherin promoter (eCTGF KO mice). Lack of vascular endothelial-derived CTGF protected against the development of PH secondary to chronic hypoxia, as well as in another model of bleomycin-induced pulmonary hypertension. Importantly, attenuation of PH was associated with a decrease in infiltrating inflammatory cells expressing CD11b or integrin M (ITGAM), a known adhesion receptor for CTGF, in the lungs of hypoxia-exposed eCTGF KO mice. Moreover, these pathological changes were associated with activation of – Rho GTPase family member – cell division control protein 42 homolog (Cdc42) signaling, known to be associated with alteration in endothelial barrier function. 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 Cdc42 activity. Based on our studies, CTGF inhibitor treatment should be investigated in patients with PH associated with chronic hypoxia secondary to chronic lung disease.

Keywords: pulmonary hypertension, hypoxia, Connective tissue growth factor (CTGF), CD11b/integrin M (ITGAM), cell division control protein 42 homolog (Cdc42)

Received: 30 Nov 2017; Accepted: 12 Feb 2018.

Edited by:

Harry Karmouty Quintana, University of Texas Health Science Center at Houston, United States

Reviewed by:

Giuseppina Milano, Centre Hospitalier Universitaire Vaudois (CHUV), Switzerland
Chuen-Mao Yang, Chang Gung University, Taiwan  

Copyright: © 2018 Pi, Fu, Lu, Zhou, Jorgensen, Shenoy, Lipson, Scott and Bryant. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Andrew J. Bryant, University of Florida, Gainesville, United States,