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Endothelial Fibroblast Growth Factor Receptor 1 Promotes Chronic Hypoxia Induced Pulmonary Arterial Hypertension Involving Estrogen Receptors
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A2096 - Endothelial Fibroblast Growth Factor Receptor 1 Promotes Chronic Hypoxia Induced Pulmonary Arterial Hypertension Involving Estrogen Receptors
Author Block: A. Racanelli1, D. Chavez2, P. Guo2, B. Ding2, A. M. Choi1; 1Joan and Sanford I. Weill Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College-New York Presbyterian Hospital, New York, NY, United States, 2Joan and Sanford I. Weill Department of Medicine, Division of Regenerative Medicine, Weill Cornell Medical College, New York, NY, United States.
Rationale:
Pulmonary hypertension (PH) is a fatal disease characterized by vascular remodeling, leading to a rise in pulmonary vascular resistance and right ventricular failure. PH affects over one-hundred million people worldwide and the current treatments available provide mainly symptomatic relief. The discovery of new therapies is critical and relies on further identification of the cellular and molecular mechanisms involved.
Non-canonical functions of vascular endothelial cells (ECs) as drivers of organ regeneration and repair have been illustrated in multiple organs. The release of organ-specific growth factors, known as angiocrine factors, by local ECs drive tissue homeostasis and regeneration (Ding, BS et.al, 2011 and Nolan, DJ, et.al, 2013) . On the contrary, dysregulated ECs are linked to a maladaptive niche resulting in fibrosis and tumorigenesis (Cao et al, 2014). The EC derived fibroblast growth factor (FGF2), a known angiocrine factor, and one of its receptors fibroblast growth factor receptor-1 (FGFR1) is known to be activated in human PH samples (Izziki et al, 2009(Izziki et al, 2009)). However, the mechanism(s) by which EC FGFR1 mediates pathogenesis of PH remains poorly understood. We hypothesized that EC FGFR1 activation is key in creating the vascular aberrations found in PH.
Methods:
We utilized a knockout mouse line in which FGFR1 (Fgfr1iΔEC/iΔEC) was deleted in adult mouse ECs following injection with tamoxifen (Ding BS et al, 2011). Mice were exposed to hypoxic conditions (FiO2 0.1) for 3.5 weeks and we characterized the development and severity of PH by measuring right ventricular systolic pressure (RVSP) and by assessing right ventricular remodeling using the Fulton index. Additionally, we employed the use of RNA sequencing and metabolomics analyses using isolated lung ECs from hypoxia exposed Fgfr1iΔEC/iΔEC mice compared to controls.
Results:
Fgfr1iΔEC/iΔEC mice were protected from hypoxia induced PH, evidenced by a reduction in RVSP and right ventricular remodeling when compared to normoxia controls. To elucidate the underlying mechanism(s) by which FGFR1 regulates the phenotypic responses observed, we have analyzed transcriptional and metabolic profiles in isolated lung ECs from hypoxia exposed Fgfr1iΔEC/iΔEC mice compared to controls. Our initial data suggests a link between FGFR1 levels and the estrogen receptor pathways.
Conclusions:
We conclude that EC FGFR1 is a key driver of hypoxia induced PH and our future studies will involve testing the efficacy of readily available FGFR1 inhibitors in the prevention of PH in our murine model.
Author Block: A. Racanelli1, D. Chavez2, P. Guo2, B. Ding2, A. M. Choi1; 1Joan and Sanford I. Weill Department of Medicine, Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College-New York Presbyterian Hospital, New York, NY, United States, 2Joan and Sanford I. Weill Department of Medicine, Division of Regenerative Medicine, Weill Cornell Medical College, New York, NY, United States.
Rationale:
Pulmonary hypertension (PH) is a fatal disease characterized by vascular remodeling, leading to a rise in pulmonary vascular resistance and right ventricular failure. PH affects over one-hundred million people worldwide and the current treatments available provide mainly symptomatic relief. The discovery of new therapies is critical and relies on further identification of the cellular and molecular mechanisms involved.
Non-canonical functions of vascular endothelial cells (ECs) as drivers of organ regeneration and repair have been illustrated in multiple organs. The release of organ-specific growth factors, known as angiocrine factors, by local ECs drive tissue homeostasis and regeneration (Ding, BS et.al, 2011 and Nolan, DJ, et.al, 2013) . On the contrary, dysregulated ECs are linked to a maladaptive niche resulting in fibrosis and tumorigenesis (Cao et al, 2014). The EC derived fibroblast growth factor (FGF2), a known angiocrine factor, and one of its receptors fibroblast growth factor receptor-1 (FGFR1) is known to be activated in human PH samples (Izziki et al, 2009(Izziki et al, 2009)). However, the mechanism(s) by which EC FGFR1 mediates pathogenesis of PH remains poorly understood. We hypothesized that EC FGFR1 activation is key in creating the vascular aberrations found in PH.
Methods:
We utilized a knockout mouse line in which FGFR1 (Fgfr1iΔEC/iΔEC) was deleted in adult mouse ECs following injection with tamoxifen (Ding BS et al, 2011). Mice were exposed to hypoxic conditions (FiO2 0.1) for 3.5 weeks and we characterized the development and severity of PH by measuring right ventricular systolic pressure (RVSP) and by assessing right ventricular remodeling using the Fulton index. Additionally, we employed the use of RNA sequencing and metabolomics analyses using isolated lung ECs from hypoxia exposed Fgfr1iΔEC/iΔEC mice compared to controls.
Results:
Fgfr1iΔEC/iΔEC mice were protected from hypoxia induced PH, evidenced by a reduction in RVSP and right ventricular remodeling when compared to normoxia controls. To elucidate the underlying mechanism(s) by which FGFR1 regulates the phenotypic responses observed, we have analyzed transcriptional and metabolic profiles in isolated lung ECs from hypoxia exposed Fgfr1iΔEC/iΔEC mice compared to controls. Our initial data suggests a link between FGFR1 levels and the estrogen receptor pathways.
Conclusions:
We conclude that EC FGFR1 is a key driver of hypoxia induced PH and our future studies will involve testing the efficacy of readily available FGFR1 inhibitors in the prevention of PH in our murine model.
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